Author byline as per print journal: Mansour Somaily1, MD; Hana Alahmari1, MD; Wejdan Abbag2; Shahenda Yousif4, MD; Nawar Tayfour4, MD; Nouf Almushayt2; Saleh Alhusayni3, MD; Saeed Almajadiah4, MD
Background: A biosimilar version of infliximab (CT-P13) was recently approved for use in Saudi Arabia. Clinical data support its use in the treatment of rheumatic disease, however, there is a lack of local data regarding the efficacy and tolerability of CT-P13 among patients with rheumatological disorders in Saudi Arabia. Objectives: To investigate the feasibility, tolerability and immunogenicity of switching from originator infliximab to biosimilar infliximab, CT-P13, in patients with rheumatoid arthritis (RA), ankylosing spondylitis (AS) and Behçet’s disease. Methodology: The study included patients who were being treated with originator infliximab in the Department of Rheumatology in Khamis Mushayt General Hospital, Saudi Arabia, and were required to switch to biosimilar infliximab (CT-P13) between January 2018 and June 2019. Patient follow-up was carried out every three months for one year. The disease activity score 28 (DAS28) was used to assess RA severity. The Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score was used to measure disease activity in patients with AS, while Behçet’s disease activity was based on clinical assessment. Results: In total, 13 patients (six with RA, five with AS and two with BD) were switched to biosimilar infliximab. The majority (n = 11/13) remained on biosimilar infliximab throughout the follow-up period with no reported major adverse events. Overall, there was a significant improvement in RA disease activity following biosimilar treatment, with the mean DAS28 decreasing from 3.61±1.24 before biosimilar therapy to 2.63±1.54 one year after switching. Conclusion: In patients with AS, BD, or RA who switched from originator infliximab to the biosimilar, CT-P13, we did not observe any significant differences in tolerability or efficacy between biosimilar and originator. Furthermore, disease activity significantly declined in RA patients following biosimilar treatment.
Submitted: 16 September 2020; Revised: 30 January 2021; Accepted: 8 February 2021; Published online first: 22 February 2021
Introduction
Tumour necrosis factor (TNF) is an inflammatory cytokine involved in the pathogenesis of rheumatoid arthritis (RA) [11]. It is produced by a number of cell types in the human body, including those in the synovial membrane and fluid of RA patients [2, 3]. Blocking TNF has been shown to have anti-inflammatory and protective effects in RA [4]. TNF is also important in the pathogenesis of ankylosing spondylitis (AS) [5] and previous studies have identified high levels of TNF mRNA expression near the site of new bone formation and increased TNF protein levels in serum in patients with AS [6, 7].
Infliximab was one of the first TNF inhibitors (TNFI) to be used clinically for the treatment of RA, AS and other inflammatory diseases [8]. In 2013, the first infliximab biosimilar, CT-P13, was approved by the European Medicines Agency (EMA) based on randomized controlled trials in RA and AS, demonstrating no statistically significant differences in safety profile compared with the originator [9-11].
CT-P13 was launched on the market in Saudi Arabia at the end of 2016. Clinical data support its use in the treatment of a number of rheumatological diseases, however, there is a lack of local data regarding its safety profile and efficacy among patients in Saudi Arabia. Therefore, the present study was carried out to explore the pharmacological, therapeutic and clinical effects of CT-P13 in patients with RA, AS and BD, encountered during clinical practice in the Department of Rheumatology in Khamis Mushayt General Hospital, Saudi Arabia.
Methodology
This study included 13 patients seen at the Department of Rheumatology in Khamis Mushayt General Hospital. All patients were being treated with originator infliximab and were required to switch to the biosimilar version due to the originator becoming unavailable. Patients were recruited between January 2018 and June 2019. Biosimilar infliximab was given as a standard (3–7.5 mg/kg) IV infusion every 8 weeks. Patients were followed up once every three months, for 12 months.
The RA disease activity score 28 (DAS28) was used for clinical assessment of RA patients. The DAS28, which is a validated tool to define remission in established cases of RA, includes measurement of the number of swollen and tender joints, levels of inflammatory markers in blood (Erythrocyte Sedimentation Rate (ESR)), and assessment of patient general health.
Assessment of AS patients was dependent on the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score. This clinically validated index takes into account fatigue, neck, back and hip pain, and other joint symptoms, in addition to assessment of overall discomfort, e.g. areas tender to touch.
The assessment of BD patients depended on clinical assessment of the major manifestations of BD, such as orogenital ulceration, and ocular, musculoskeletal and cutaneous manifestations.
Information about infliximab and its possible adverse effects were described in detail and consents were given in all cases. The study proposal was also approved by the Research Ethics Local Committee, College of Medicine, University of Bisha.
The Shapiro-Wilk test revealed that the data were abnormally distributed. As such, a Wilcoxon signed ranks test was used to compare clinical scores before and after starting treatment with the biosimilar (CT-P13). A p-value < 0.05 was considered significant in all cases.
Results
In total, 13 patients (six with RA, five with AS and two with BD) were switched to biosimilar infliximab (CT-P13) between January 2018 and June 2019. Table 1 summarizes the demographic and clinical characteristics of the patients. Patients were aged between 25 and 55 years (mean age = 39.7±11.7) and 61.5% were women. The majority (n = 11/13) maintained treatment with CT-P13 throughout the follow-up period with no reported major adverse events, excluding two patients with RA who had upper respiratory infection.
Table 2 shows significant improvement in RA disease activity, as measured by the DAS28. The mean DAS28 score was 3.61±1.24 prior to infliximab biosimilar therapy, which reduced to 2.63±1.54 at one year of follow-up (p = 0.046).
Discussion
Several studies have assessed the safety, efficacy and immunogenicity of switching from the infliximab originator to the CT-P13 biosimilar version. However, the majority of these studies have not included control arms and have been observational in nature, in addition to investigating a single switch only. Importantly for Saudi Arabia, none of these studies were carried out in the locality. Therefore, this study was carried out to investigate the therapeutic and clinical effects of CT-P13 in patients with RA, SA and BD, and demonstrates local experience with the biosimilar.
A number of previous studies have investigated the effects of switching between the infliximab originator and the biosimilar, CT-P13. For example, in the second-year extension to the PLANETAS study [12], adverse events associated with biosimilar treatment were observed in 71.4% of patients who switched compared with 48.9% of those who continued receiving treatment with the originator. In addition, in the DANBIO register [13], approximately 6% of patients stopped treatment within three months of switching from originator infliximab to CT-P13 due to adverse events or lack of efficacy. In a study carried out on AS patients who switched from originator infliximab to its biosimilar, 11% of patients from the biosimilar group and 7% of the reference group discontinued the study during the 18-month follow-up period. Of those who discontinued biosimilar treatment, 80% did so due to adverse effects and 20% because of loss of efficacy [14].
The present case study did not identify any statistically significant differences in efficacy or tolerability between CT-P13 and originator infliximab in this small group of subjects in Saudi Arabia. This is in line with previous studies, such as the work of Jørgensen KK et al. [15], who reported that, according to a prespecified non-inferiority margin of 15%, the frequency of serious adverse events was not statistically different between patients treated with originator infliximab and those treated with CT-P13.
Additional observational studies and data from the extensions of the PLANETRA and PLANETAS studies identified few concerns regarding the efficacy and/or safety of CT-P13 [12, 16-19]. A recent systematic literature review including 70 full articles or abstracts evaluated the safety and efficacy of switching between originator and biosimilar infliximab in patients with inflammatory disorders. This review reported that most studies were observational, not containing a control group, and included only six randomized controlled trials (RCTs). It also concluded that no clinically relevant efficacy or safety concerns were associated with switching [20].
An additional survey carried out among adult patients in the United States (US) with RA, AS, and psoriatic arthritis who switched from infliximab to infliximab-dyyb biosimilar therapy evaluated the safety and efficacy of the biosimilar treatment, as well as patient awareness of biosimilar therapy. This paper concluded that patients were generally satisfied with their current therapy, whether this was originator infliximab or infliximab-dyyb. However, patients had concerns about switching, in particular, relating to price, safety, and efficacy [21].
The present study reported improvement in RA disease activity following biosimilar treatment (mean DAS28 of 3.61±1.24 prior to switching, compared to 2.63±1.54 one-year post-switching). However, another RCT identified no significant change in DAS28 between RA patients treated with the originator and those treated with the biosimilar [22].
In addition, in the present study, the five patients with AS who were switched from the originator to its biosimilar exhibited an improvement in their disease activity index (the BASDAI mean score reduced from 3.3±0.7 before biosimilar therapy to 0.28±0.52 after one year of biosimilar therapy, however, the result was not significant), see Table 3. This can be compared to the results of another study, where the BASDAI score was 3.7±0.4 in a group of AS patients treated with biosimilar infliximab, compared to 3.8±0.2 among those treated with the originator [23].
In terms of limitations, this study includes data from a limited number of patients (n = 13) and was not randomized nor double-blinded. However, the aim of the study is to report experiences with switching to biosimilar infliximab in Saudi Arabia, which has not previously been examined. The findings from this study suggest that CT-P13 has comparable tolerability and efficacy to originator infliximab and may reduce disease activity in RA patients. However, a larger, double-blind RCT is recommended to ensure the safety and efficacy of the biosimilar. These findings provide important preliminary data and are considered the first evidence (after a literature search in the PubMed and Google Scholar) on switching between originator infliximab to a biosimilar infliximab product in Saudi Arabia.
Conclusion
The findings from this study suggest that CT-P13 has comparable tolerability and efficacy to originator infliximab and may reduce disease activity in RA patients. However, a larger double-blind randomised controlled trial (RCT) is recommended to ensure the safety and efficacy of the biosimilar. These important preliminary data are considered the first evidence (based on a literature search of PubMed and Google Scholar conducted up to November 2020) on switching from originator infliximab to a biosimilar infliximab product in Saudi Arabia.
Ethics approval
This study received approval of the ethical clearance from the Research Ethics Local Committee of the College of Medicine, University of Bisha (UBCOM-RELOC) (registration no. H-06-BH-087) based on the recommendation of the committee issued on 15 August 2020.
Competing interests: There was no support of any kinds (including for presentation of data, travel or publication) provided to any of the authors by the manufacturer prior to or after the study was conducted.
Provenance and peer review: Not commissioned; externally peer reviewed.
1Department of Medicine, Rheumatology Division, King Khalid University Medical City, 3294 Al Muruj District, Unit number 300, Building No. 8294, 62527-3989 Abha, Saudi Arabia 2College of Medicine, King Khalid University, Almahala Street, 62562 Aseer-Abha, Saudi Arabia 3Asser Central Hospital, Bani Malik Street, 62526 Abha, Saudi Arabia 4Department of Medicine, Rheumatology Division, Khamis Mushayt General Hospital, Almahala Street, 62562 Aseer-Abha, Saudi Arabia
References 1. Smolen JS, Steiner G. Therapeutic strategies for rheumatoid arthritis. Nat Rev Drug Discov. 2003;2(6):473-88. 2. Chu CQ, Field M, Feldmann M, Maini RN. Localization of tumor necrosis factor alpha in synovial tissues and at the cartilage-pannus junction in patients with rheumatoid arthritis. Arthritis Rheum. 1991;34(9):1125-32. 3. Saxne T, Palladino MA Jr, Heinegård D,Talal N, Wollheim FA. Detection of tumor necrosis factor alpha but not tumor necrosis factor beta in rheumatoid arthritis synovial fluid and serum. Arthritis Rheum. 1988;31:1041-5. 4. Feldmann M, Maini RN. Anti-TNF alpha therapy of rheumatoid arthritis: what have we learned? Annu Rev Immunol. 2001;19:163-96. 5. Hreggvidsdottir HS, Noordenbos T, Baeten DL. Inflammatory pathways in spondyloarthritis. Mol Immunol. 2014;57(1):28-37. 6. Gratacós J, Collado A, Filella X, Sanmartí R, Cañete J, Llena J, et al. Serum cytokines (IL-6, TNF-alpha, IL-1 beta and IFN-gamma) in ankylosing spondylitis: a close correlation between serum IL-6 and disease activity and severity. Br J Rheumatol. 1994;33(10):927-31. 7. Braun J, Bollow M, Neure L, Seipelt E, Seyrekbasan F, Herbst H, et al. Use of immunohistologic and in situ hybridization techniques in the examination of sacroiliac joint biopsy specimens from patients with ankylosing spondylitis. Arthritis Rheum. 1995;38(4):499-505. 8. Yoo DH, Oh C, Hong SS, Park W. Analysis of clinical trials of biosimilar infliximab (CT-P13) and comparison against historical clinical studies with the infliximab reference medicinal product. Expert Rev Clin Immunol. 2015;11 Supp1:S15-24. 9. European Medicines Agency. Committee for Medicinal Products for Human Use (CHMP). Assessment report: Remsima (infliximab). 27 June 2013. EMA/CHMP/589317/2013 [homepage on the Internet]. [cited 2021 Jan 30]. Available from: www.ema.europa.eu/docs/en_GB/document_library/EPAR_Public_assessmentreport/human/002576/ WC500151486.pdf 10. Yoo DH, Hrycaj P, Miranda P, Ramiterre E, Piotrowski M, Shevchuk, S, et al. A randomised, double-blind, parallel-group study to demonstrate equivalence in efficacy and safety of CT-P13 compared with innovator infliximab when coadministered with methotrexate in patients with active rheumatoid arthritis: the PLANETRA study. Ann Rheum Dis. 2013;72(10):1613-20. 11. Park W, Hrycaj P, Jeka S, Kovalenko V, Lysenko G, Pedro Miranda P, et al. A randomised, double-blind, multicentre, parallel-group, prospective study comparing the pharmacokinetics, safety, and efficacy of CT-P13 and innovator infliximab in patients with ankylosing spondylitis: the PLANETAS study. Ann Rheum Dis. 2013;72(10):1605-12. 12. Park W, Yoo DH, Miranda P, Brzosko M, Wiland P, Gutierrez-Ureña S, et al. Efficacy and safety of switching from reference infliximab to CT-P13 compared with maintenance of CT-P13 in ankylosing spondylitis: 102-week data from the PLANETAS extension study. Ann Rheum Dis. 2017;76(2):346-54. 13. Glintborg B, Juul Sørensen I, Vendelbo Jensen D, Krogh NS, Loft AG, et al. Three months’ clinical outcomes from a nationwide non-medical switch from originator to biosimilar infliximab in patients with inflammatory arthritis, results from the DANBIO registry. Ann Rheum Dis. 2016;75(Suppl 2):142. 14. Kaltsonoudis E, Pelechas E, Voulgari PV, Drosos AA. Maintained clinical remission in ankylosing spondylitis patients switched from reference Infliximab to its biosimilar: an 18-month comparative open-label study. J Clin Med. 2019;8(7):956. 15. Jørgensen KK, Olsen IC, Goll GL, Lorentzen M, Bolstad N, Haavardsholm EA, et al. Switching from originator infliximab to biosimilar CT-P13 compared with maintained treatment with originator infliximab (NOR-SWITCH): a 52-week, randomised, double-blind, non-inferiority trial. Lancet. 2017;389(10086):2304-16. 16. Buer LC, Moum BA, Cvancarova M, Warren DJ, Medhus AW, Hoivik ML. Switching from Remicade® to Remsima® is well tolerated and feasible: a prospective, open-label study. J Crohns Colitis. 2017;11(3):297-304. 17. Smits LJT, Derikx LAA, de Jong DJ, Boshuizen RS, van Esch AAJ, Drenth, JPH, et al. Clinical outcomes following a switch from Remicade® to the biosimilar CT-P13 in inflammatory bowel disease patients: a prospective observational cohort study. J Crohns Colitis. 2016;10:1287-93. 18. Yoo DH, Prodanovic N, Jaworski J, Miranda P, Ramiterre E, Lanzon A, et al. Efficacy and safety of CT-P13 (biosimilar infliximab) in patients with rheumatoid arthritis: comparison between switching from reference infliximab to CT-P13 and continuing CT-P13 in the PLANETRA extension study. Ann Rheum Dis. 2017;76(2):355-63. 19. Vergara-Dangond C, Sáez Bello M, Climente Martí M, Llopis Salvia P, Alegre-Sancho JJ. Effectiveness and safety of switching from innovator infliximab to biosimilar CT-P13 in inflammatory rheumatic diseases: a real‐world case study. Drugs R D. 2017;17(3):481-5. 20. Feagan BG, Lam G, Ma C, Lichtenstein GR. Systematic review: efficacy and safety of switching patients between reference and biosimilar infliximab. Aliment Pharmacol Ther. 2019;49(1):31-40. 21. Chau J, Delate T, Ota T, Bhardwaja B. Patient perspectives on switching from Infliximab to Infliximab-dyyb in patients with rheumatologic diseases in the United States. ACR Open Rheumatol. 2019;1(1):52-7. 22. Genovese MC, Sanchez-Burson J, Oh MS, Balazs E, Neal J, Everding A, et al. Comparative clinical efficacy and safety of the proposed biosimilar ABP 710 with infliximab reference product in patients with rheumatoid arthritis. Arthritis Res Ther. 2020;22(1):60. 23. Kaltsonoudis E, Pelechas E, Voulgari PV, Drosos AA. Maintained clinical remission in ankylosing spondylitis patients switched from reference Infliximab to its biosimilar: an 18-month comparative open-label study. J Clin Med. 2019;8(7):956.
Author for correspondence: Mansour Somaily, MD, Consultant, Department of Medicine, Rheumatology Division, King Khalid University Medical City, 3294 Al Muruj District, Unit number 300, Building No. 8294, 62527-3989 Abha, Saudi Arabia
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Author byline as per print journal: Brian Godman1,2,3, BSc, PhD; Steven Simoens4, MSc, PhD; Amanj Kurdi1,5, BSc, PhD; Gisbert Selke6; John Yfantopoulos7, PhD; Andrew Hill8, PhD; Jolanta Gulbinovič9, MD, PhD; Antony P Martin10,11, MA, PhD1; Angela Timoney1,12, BPharm, PhD; Dzintars Gotham13, MBBS; Janet Wale14, PhD; Tomasz Bochenek15, PhD; Iva Selke Krulichova16, MSc, PhD; Eleonora Allocati17, MSc; Iris Hoxha18; Admir Malaj19; Christian Hierlander20; Anna Nachtnebel20, MSc, MD; Wouter Hamelinck21, MSc; Zornitza Mitkova22, PhD; Guenka Petrova22, PhD; Ott Laius23, PhD; Catherine Sermet24, MD, PhD; Irene Langner6; Roberta Joppi25, PhD; Arianit Jakupi26; Elita Poplavska27, PhD; Ieva Greiciute-Kuprijanov28; Patricia Vella Bonanno1, PhD; JF (Hans) Piepenbrink29; Vincent de Valk29; Robert Plisko30, Magdalene Wladysiuk30, MD, PhD; Vanda Marković-Peković31, PhD; Ileana Mardare32, PhD; Tanja Novakovic33; Mark Parker33; Jurij Furst34; Dominik Tomek35, PharmD, MSc, PhD; Katarina Banasova36; Merce Obach Cortadellas37; Corrine Zara37; Caridad Pontes37,38; Maria Juhasz-Haverinen39, MScPharm; Peter Skiold40, BSc; Stuart McTaggart41; Durhane Wong-Rieger42; Stephen Campbell43,44, PhD; Ruaraidh Hill45, PhD
Introduction/Objectives: Health authorities are facing increasing challenges to the sustainability of their healthcare systems because of the growing expenditures on medicines, including new, high-priced oncology medicines, and changes in disease prevalence in their ageing populations. Medicine prices in European countries are greatly affected by the ability to negotiate reasonable prices. Concerns have been expressed that prices of patented medicines do not fall sufficiently after the introduction of lower-cost generic oncology medicines. The objective of this study was to examine the associations over time in selected European countries between the prices of oral oncology medicines, population size, and gross domestic product (GDP) before and after the introduction of generic versions. Evidence of periodic reassessments of the price, value, and place in treatment of these medicines was also looked for. The goal of this review was to stimulate debate about possible improvements in approaches to reimbursement negotiations. Methodology: Analysis was performed of reimbursed prices of three oral oncology medicines (imatinib, erlotinib and fludarabine) between 2013 and 2017 across Europe. Correlations were explored between GDP, population size, and prices. Findings were compared with previous research regarding prices of generic oral oncology medicines. Results: The prices of imatinib, erlotinib and fludarabine varied among European countries, and there was limited price erosion over time in the absence of generics. There appeared to be no correlation between population size and price, but higher prices of on-patent oral cancer medicines were seen among countries with higher GDP per capita. Conclusion: Limited price erosion for patented medicines contributed to increases in oncology medicine budgets across the region. There was also a concerning lack of evidence re-assessments of the price, value, and place in treatment of patented oncology medicines following the loss of patent protection of standard medicines. The use of such proactive re-assessments in negotiating tactics might positively impact global expenditures for oncology medicines.
Submitted: 11 October 2020; Revised: 21 January 2021; Accepted: 21 January 2021; Published online first: 3 February 2021
Introduction/Objectives
Globally, increases in expenditure on medicines has accelerated in recent years. Expenditures have been driven principally by increased prescribing volumes and the high prices of new medicines, especially those for oncology and orphan diseases [1-4]. The prices of new oncology medicines have risen ten-fold or more during the last decade [5-8], with prices per life year gained rising four-fold during the last twenty years after adjusting for inflation [6, 9]. As a result, expenditure on oncology medicines now dominates pharmaceutical expenditure in high income countries. Expenditure is expected to accelerate as there are over 500 companies actively pursuing new oncology medicines for over 600 indications [10, 11], all with high price expectations [12, 13]. The continuously rising cost of cancer care already accounts for up to 30% of the total hospital expenditure across Europe [14, 15], and global expenditure on oncology medicines is estimated to reach US$237 billion by 2024 [16].
This growth is putting considerable strain on universal access to European healthcare systems [4, 13, 17, 18]; leading to increasing calls for prices to be linked to minimum improvements in clinical benefits, such as a minimum of three to six months additional survival [19-23]. Such linkage would reverse recent policies in European countries (based on the emotive nature of this disease area) that have funded payments even for new, high-priced cancer medicines that offer limited health gains [12, 24]. Sustainability concerns have led to world-wide calls for alternative pricing and funding approaches to new oncology medicines, including fair pricing models [25-30]. Fair pricing models necessarily include greater transparency in how prices are set; a goal of the World Health Organization (WHO).
WHO has called for improved access to new medicines for all patients, including those with cancer [31, 32]. Calls for fairer pricing of new medicines are growing; based on recognition of both the low production cost of some cancer medicines (due to low costs of raw materials and improved manufacturing), and the appreciable discounting of original biological medicines by pharmaceutical companies that have occurred after the introduction of biosimilar competition [33-35].
Excessive pricing is particularly problematic in the US where prices for both existing on-patent oncology medicines as well as new cancer medicines continue to increase rapidly as a result of a lack of formal pricing and reimbursement processes. US oncologists have requested price moderation for new oncology medicines [36]; however, this has failed to materialize. By recent estimates, net expenditure in the US would be US$39.5 billion for 46 new oncology medicines approved in 2018 (17 novel medications and 29 new indications for existing medications), if all eligible patients received them [37]. Potential expenditure in 2018 on oncology medicines in the US could have been even greater, as this figure does not include the cost of other oncology medicines [37].
In Europe, when prices for medicines are established, there appears to be limited price erosion until multiple source products become available. This is unlike the situation in the US [38, 39]. There also appear to be limited differences between European countries regarding prices for patented biological oncology medicines. For example, it was reported that there was only a 13% difference between the prices for various medicines, including bevacizumab and ipilimumab, across 16 European countries while there were much greater differences for lower-priced medicines [40]. Similarly, limited differences were observed in the monthly treatment costs for new oncology medicines among European countries. However, the costs of medicines in the US were a median of 2.31 times higher than those seen in Europe, reflecting the current lack of pricing controls in the US [39, 41]. The situation in Europe may reflect extensive external reference pricing for new medicines [30, 42], although considerable differences in the pricing of multi-sourced oncology medicines exist among European countries [34].
Prices of cancer medicines have recently been reviewed in a number of publications [38, 40, 41]. There is a need to build on these findings to provide useful guidance for health authorities as they struggle with their budgets for oncology medicines. This includes assessing the potential influence of gross domestic product (GDP) and population size on reimbursed prices of patented medicines across Europe. This is important because countries with smaller populations and less economic power could be at a disadvantage during pricing negotiations. If true, this could result in higher negotiated prices despite the existence of extensive external reference pricing data across Europe [41, 42]. These concerns triggered the development of cross-country European consortia, designed to enhance negotiating power for new, premium-priced medicines [43]. These consortia include Beneluxa, Valleta and the Nordic consortium [32, 43-45]. It has been shown that the prices of oral generic cancer medicines were not dependant on the European country’s population size or their economic status and that, over time, appreciable price reductions were observed [34]. However, this trend may be different for on-patent oral cancer medicines.
Given the unsustainability of current systems, it is hoped that this review can stimulate further debate regarding possible new approaches to reimbursement negotiations. Debate should include how the negotiation of prices of existing patented oncology medicines should change after a standard oncology medicine loses its patent protection, potentially appreciably altering the cost-effectiveness ratio of existing patented medicines and their overall value. In addition, the pricing of new, on-patent oncology medicines across Europe should consider the use of fair pricing models. This review builds on current initiatives from WHO, the European Commission, and European insurers, that all call for greater transparency in pricing negotiations [18, 22, 26, 32].
Europe was chosen for study because of its goals of providing equitable and universal healthcare; including for patients with oncologic and rare diseases. Europe has also introduced multiple, ongoing activities designed to improve the quality and efficiency of prescribing of both new and established medicines [20, 21, 30, 46-50]. In addition, European countries have formal pricing and reimbursement processes in place and there are processes in place to review and refine approaches within the jurisdiction of each Member State [30, 39, 51]. This contrasts with the US, which currently has no formal pricing or reimbursement systems in place. As a result of this deficiency, the US is currently responsible for over 40% of global pharmaceutical spending despite having only 4.5% of the world’s population [39].
This study represents a payer perspective since payers are the key stakeholders involved in funding and reimbursement decisions for oncology medicines across Europe. Health authority databases were used as they are regularly audited and reflect the prices paid by health authorities for these medicines with or without value added tax (VAT), depending on the country [34, 52-54].
Methodology
The methodology used has been previously described [34]. The European countries examined were Albania, Austria, Belgium, B&H (Republic of Srpska), Bulgaria, Cyprus, Estonia, France, Germany, Greece, Italy, Kosovo, Latvia, Lithuania, Malta, Netherlands, Norway, Poland, Romania, Serbia, Slovenia, Slovakia, Spain (represented by pricing data from Catalonia with list prices similar across Spain), Sweden, and Scotland [as a representative of the United Kingdom (UK) as tariff prices are consistent across the UK]. The countries chosen include a wide range of geographies, populations, and GDPs. They also provided access to robust data from their administrative databases. Pricing data from health authorities are reliable and robust because their systems are regularly audited [34, 55]. This approach has also been used previously in multiple cross-national publications assessing utilization and expenditure patterns for different medicines and disease areas across Europe [34,52-54, 56-58].
This study concentrated on reimbursed prices for imatinib (L01XE01), erlotinib (L01XE03) and fludarabine (L01BB05) in Western European countries [59]. Generics were unavailable in 2015 for imatinib, and in 2017 for erlotinib and fludarabine. External reference pricing is infrequently used in these countries [34, 42, 52]. The delayed availability of generic versions of these oral cancer medicines in Western European countries provided a longer time period over which any price erosion could be monitored. These data build on earlier findings that involved assessing reimbursed prices for generic busulfan (L01AB01), capecitabine (L01BC06), chlorambucil (L01AA02), cyclophosphamide (L01AA01), flutamide (L02BB01), imatinib (L01XE01), melphalan (L01AA03), and temozolomide (L01AX03) over time across Europe [34].
Reimbursed prices were used where possible. However, in a minority of countries, procured and total prices were used instead (e.g. Kosovo) when it was not possible to break prices down into individual components. Total prices include pharmacy remuneration and any patient co-payments. In some countries, VAT was also included in the price. In some cases it was difficult to determine the exact proportion for each component to the total price from the information provided. Documented prices could also include any discounted prices arising from managed entry agreements (MEAs); sometimes referred to as risk sharing arrangements [50, 60]. However, MEAs were rare for individual oncology medicines in Europe prior to the recent rapid increase in the requested prices for new oncology medicines [60-63]. In some countries, reimbursed prices were listed, but the medicines are typically dispensed in hospitals where further, confidential discounts are provided, such as in Norway and Italy.
Reimbursed prices were generally recorded between 2013 and 2017 and were based on tablet strength. Tablet strengths were chosen for comparative purposes as opposed to defined daily doses (DDDs) used in previous cross-national research [52-54, 56, 57], as generally there are no DDDs for oral cancer medicines [59]. The tablet strength chosen reflects the most commonly used strength.
Initially, prices were documented in the country’s currency if not listed in Euros. Subsequently, where relevant, prices were converted to Euros for comparative purposes based on current exchange rates and were validated by co-authors to enhance the robustness of the findings [34, 64-71]. Prices were then converted to US$ based on mid-year European Central Bank exchange rates for comparison with the Organisation for Economic Co-operation and Development (OECD) GDP per capita data for 2015 and 2017 [72-74]. However, prices were retained in Euros when calculating any price erosion of the on-patent oral oncology medicines over time. Euros were also used for comparing prices of different generic oral cancer medicines, as one of the principal aims of this study was to compare prices across countries, as well to consider any price reductions achieved [34].
The OECD data on GDP per capita in US$ in 2015 and 2017 were supplemented with additional data if OECD data for these years were not available [72], e.g. 2018 OECD data were used for Albania and Cyprus and alternate data sources were used for Kosovo, Malta, Romania, and Serbia [75-78]. For consistency, the OECD data were also used for population sizes in 2015 and 2017; however, data from other sources was also used where required [78-81]. Country abbreviations were based on the International Organization for Standardization abbreviations, see Table 1A in the Appendix, [82].
Differences in country prices were visualised as violin plots to enhance interpretation of the data. Non-parametric Spearman’s rank tests were used to assess any correlation between prices and the countries’ population size, as well as their GDP per capita. Correlations were presented as Spearman’s rank correlation coefficients which range from -1 (perfect negative correlation) to +1 (perfect positive correlation). A p-value less than 0.05 was considered statistically significant. No correction for multiple comparisons was made. The correlations were also visually presented using scatter plots. Calculations were performed using R 3.6.1 software [83].
No ethical approval was obtained since only aggregate, anonymised data were used. This is in accordance with methods used in similar studies using administrative databases [34, 46, 53, 56, 84]. The definition of terms used, including external reference pricing, managed entry agreements (MEAs), and value-based pricing, follow those used for reforms and initiatives introduced across Europe [30].
Results
Prices of generic oral cancer medicines across Europe A prior 2019 study showed that there were variable approaches made to the pricing of generic oral oncology medicines across Europe. This situation is similar for the pricing of other generic medicines [34, 49, 52, 85, 86]. The different approaches used can be consolidated into three categories [34]:
prescriptive pricing policies (price regulated market): policies using established percentage reductions for successive generics
market forces (free market): where there is typically free pricing for generics with market forces helping to drive down prices
mixed approach (combination): that incorporates prescriptive approaches, market forces, and other mechanisms, including external reference pricing, commonly used across Europe.
Differences in the approaches adopted by the various European countries resulted in appreciable differences in the reimbursed prices for generic oral oncology medicines across Europe. In addition, appreciable differences in the price reductions were seen for generic medicines in many European countries versus prices prior to loss of patents, see Box 1.
Reimbursed prices were not indication specific, i.e. there were no differential prices once the first indication had lost its patent. In addition, contrary to prior reports [34], the generic oral oncology medicine prices in 2017 did not appear to be correlated with the country’s population size or to its GDP (Central and Eastern Europe (CEE) versus Western European countries). There were also no apparent concerns expressed about substitution with generic oral oncology medicines [34]. This is encouraging as such concerns have been reported to limit the extent of savings possible following the availability of generics [87].
Prices of originator, on-patent oral cancer medicines across Europe Imatinib Table 1 documents the prices for originator 400 mg imatinib tablets among Western European countries in 2015 prior to generic availability. Figure 1 presents the range of prices across all the countries studied. Generic imatinib was already available prior to 2015 in CEE countries, e.g. Albania, Estonia, Latvia, Lithuania, Romania, Serbia and Slovakia in 2013 or before, and in Poland and Slovenia in 2014 [34], and originator prices typically fell in these countries when generics became available [34, 49, 85].
While the minimum price of imatinib was 12.8% below the median (US$90.13), and the maximum price 4.6% above the median (excluding the outlier Germany at +38.3%), the results of the Spearman’s rank test indicated no correlation (r = –0.100; p = 0.776) between the price of imatinib and the country’s population size, see Appendix Figure 1 A. However, there was a moderate, statistically insignificant positive correlation (r = +0.527; p = 0.100) between imatinib prices and GDP per capita, see Figure 2.
Erlotinib In 2017, no generic erlotinib (150 mg) was available in the selected Western European countries or in a number of the studied CEE countries [34]. Consequently, it was possible to survey prices of this on-patent product in 16 European countries. Prices varied from 20.9% below the median price (US$73.44) to 23.2% above the median (disregarding the outliers Germany and Italy at 49.0% and 58.8%, respectively), see Table 2; Figure 1. There was no significant correlation (r = 0.303; p = 0.253) between the prices of erlotinib and country’s population size, see Figure 2A in the Appendix, but there was a significant moderate positive correlation (r = 0.532; p = 0.036) between erlotinib prices and GDP per capita, see Figure 3.
There were limited differences in prices for originator erlotinib over time in these selected Western European countries, see Table 2. However, once multiple generic versions became available in 2017, prices fell rapidly in some countries. For example, in the Republic of Srpska prices fell to 26.9% of the 2013 originator prices, and in Bulgaria, Romania, and Lithuania prices fell to 34.3%, 45.7% and 54.4% of 2013 originator price, respectively. Similar trends have been observed across Europe for other oral cancer medicines once generics became available [34].
Fludarabine In 2017, no generic fludarabine was available in Western European countries or in a number of CEE countries. As a result, prices from 16 selected European countries were included in the analysis.
Documented prices, see Table 3 and Figure 1, ranged from 53% below to 29% above the median (US$28.09). There was no correlation (r = 0.035; p = 0.900) between the price of fludarabine and population size in these selected countries, see Figure 3A, but there was a significant moderate positive correlation (r = 0.515; p = 0.044) observed between fludarabine prices and GDP per capita, see Figure 4.
Prices for both erlotinib and fludarabine were relatively stable between 2013 and 2017 in these selected Western European countries, see Table 4.
Discussion
This study investigated reimbursed prices over time for both on-patent originator and generic oral oncology medicines across a number of European countries. Contrary to prior concerns [34, 88], but consistent with other studies [41, 89, 90], prices of the three selected oral oncology medicines were not correlated with population size. It is not clear why the price differences found in this study were greater than those reported in some prior studies [40, 41]. Consequently, further research is needed to confirm these findings and whether they reflect the impact of the recent, growing implementation of external reference pricing and of MEAs [50, 61, 63].
It is counterintuitive that the prices of patented oral cancer medicines tend to be higher in countries with greater economic power, see Figures 2 to 4. These countries should have been more able to successfully negotiate confidential discounts or rebates as part of MEAs. As a result, patients in CEE countries that use prices in countries with more economic power in pricing negotiations may be faced with higher co-payments. These issues need to be further investigated and addressed. Potential solutions include greater pricing transparency coupled with growth in pan-European purchasing consortia [91, 92].
While it has been reported that there were no differences in the pricing approaches for multisource oral oncology versus non-oncology medicines, the situation differs for new, patent protected oncology medicines. Unlike in other disease areas, new oncology medicines are granted premium prices even if they provide limited health benefits [11, 12]. It is encouraging that prices for multisource products have been reported to be similar across indications, including for indications still under patent [34]. This is unlike the situation when generic versions of pregabalin were first launched, when general practitioners in some countries were threatened with legal action if they prescribed generic pregabalin for an indication still under patent [93]. The substantial price reductions (up to 98.8%) reported across Europe following the availability of oral generic oncology medicines, see Box 1[34], are also encouraging. However, care must be taken to ensure that lower prices for generic medicines do not lead to manufacturer created shortages or even the removal of oncology medicines from the market [94, 95]. In contrast to the situation seen previously with generic oral oncology medicines [34], limited price erosion was observed over time for on-patent oral oncology medicines in this study, see Table 4. Hopefully, in the future there will be greater re-evaluation of the prices of many other on-patent oncology medicines as more of these medicines that are used as benchmarks for pricing and reimbursement negotiations lose their patents [96, 97].
The need for more successful, continuously re-evaluated, value-based price negotiations will only increase as a result of the effects on healthcare systems from rising prices for new oncology medicines coupled with ageing populations and a concomitant increase in oncology disease prevalence. The potential impact of value-based pricing considerations is considerable, based on the level of price reductions that are now being seen for oral generic oncology medicines (e.g. up to 97.8%), biosimilars (e.g. 83% reduction in expenditure on adalimumab among Danish hospitals following biosimilars), and even originator medicines faced with the imminent launch of biosimilars (e.g. 89% price reduction in the Netherlands for Humira® just before biosimilars were launched) [33, 34, 98-100]. In addition, the impact is increasing because of ongoing measures in European countries to rapidly switch from use of originators to new biosimilars for both oncology and rheumatoid arthritis patients in a way that conserves valuable resources without compromising care [101-105].
Value-based pricing (VBP) means ‘ that countries set prices for new medicines and/or decide on reimbursement based on the therapeutic value which medicine offers, usually assessed through health technology assessment (HTA) or economic evaluation’ [30]. The use of VBP should result in major decreases in the prices for on-patent oncology medicines as more standard medicines used as benchmarks for pricing and reimbursement negotiations lose their patents. Alternatively, health authorities could seek appreciably greater discounts from companies for continued reimbursement of on-patent medicines as part of any existing MEA.
There are many limitations to this study, including the fact that in a minority of countries, procured and total prices had to be used because it was not possible to break prices down into individual components. VAT was also included for some countries when it was not possible to remove this component. Prices used may have been distorted somewhat when prices were converted to US$ based on mid-year European Central Bank exchange rates for comparison with GDP per capita. Information was also limited on whether or how often negotiating methods were evaluated or changed. Despite these limitations, it is thought that the findings are useful in providing direction to European health authorities responsible for negotiating and re-evaluating medicine prices and value.
Conclusion
This study has revealed that prices of on-patent oral cancer medicines tend to be higher in countries with greater economic power and the reasons behind this need to be understood. Lack of universal, substantial lowering of oral oncology medicine prices after the introduction of generic version is a concern because this contributes to increases in oncology medicine budgets across the region. Also of concern is the possible lack of re-assessments of the price, value, and place in treatment of patented oncology medicines following loss of patent protection of reference medicines. Monitoring the use of such proactive re-assessment will be increasingly essential given the likely future growth in global expenditure for oncology medicines being driven by rising cancer prevalence rates, coupled with the introduction of a number of expensive oncology medicines.
Competing interests: Most of the co-authors work for health authorities and health insurance companies across Europe or are advisers to them. Steven Simoens previously held the EGA Chair of the “European policy towards generic medicines”. All the authors have no other conflicts of interest to declare. The study was self-funded.
Provenance and peer review: Not commissioned; externally peer reviewed.
Authors
Brian Godman1,2,3, BSc, PhD Steven Simoens4, MSc, PhD Amanj Kurdi1,5, BSc, PhD Gisbert Selke6 John Yfantopoulos7, PhD Andrew Hill8, PhD Jolanta Gulbinovi9, MD, PhD Antony P Martin10,11, MA, PhD Angela Timoney1,12, BPharm, PhD Dzintars Gotham13, MBBS Janet Wale14, PhD Tomasz Bochenek15, PhD Iva Selke Krulichová16, MSc, PhD Eleonora Allocati17, MSc Iris Hoxha18 Admir Malaj19 Christian Hierländer20 Anna Nachtnebel20, MSc, MD Wouter Hamelinck21, MSc Zornitza Mitkova22, PhD Guenka Petrova22, PhD Ott Laius23, PhD Catherine Sermet24, MD, PhD Irene Langner6 Roberta Joppi25, PhD Arianit Jakupi26 Elita Poplavska27, PhD Ieva Greiciute-Kuprijanov28 Patricia Vella Bonanno1, PhD JF (Hans) Piepenbrink29 Vincent de Valk29 Robert Plisko30 Magdalene Wladysiuk30, MD, PhD Vanda Markovi31, PhD Ileana Mardare32, PhD Tanja Novakovic33 Mark Parker33 Jurij Fürst34 Dominik Tomek35, PharmD, MSc, PhD Katarina Banasova36 Mercè Obach Cortadellas37 Corrine Zara37 Caridad Pontes37,38 Maria Juhasz-Haverinen39, MScPharm Peter Skiold40, BSc Stuart McTaggart41 Durhane Wong-Rieger42 Stephen Campbell43,44, PhD Ruaraidh Hill45, PhD
1Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, 161 Cathedral Street, Glasgow G4 0RE, UK 2Division of Clinical Pharmacology, Karolinska Institute, Karolinska University Hospital Huddinge, SE-14186 Stockholm, Sweden 3School of Pharmacy, Sefako Makgatho Health Sciences University, Pretoria, Gauteng, South Africa 4KU Leuven, Department of Pharmaceutical and Pharmacological Sciences, Leuven, Belgium 5Department of Pharmacology, College of Pharmacy, Hawler Medical University, Erbil, Iraq 6Wissenschaftliches Institut der AOK (WIdO), 31 Rosenthaler Straße, DE-10178 Berlin, Germany 7School of Economics and Political Science, University of Athens, 6 Pandoras Street, Ekali, GR-14578 Athens, Greece 8Institute of Translational Medicine, University of Liverpool, UK 9Department of Pathology, Forensic Medicine and Pharmacology, Institute of Biomedical Sciences, Faculty of Medicine, Vilnius University, Suduvos g. 4-4, LT-14259 Vilnius, Lithuania 10Wolfson Centre for Personalised Medicine, University of Liverpool, Liverpool, UK 11HCD Economics, The Innovation Centre, Keckwick Ln, Daresbury, Warrington WA4 4FS, UK 12NHS Lothian Chair Scottish Intercollegiate Guidelines Network (SIGN), 2-4 Waterloo Place, Waverleygate EH1 3EG, Edinburgh, UK 13Independent researcher, London, UK 14Independent consumer advocate, 11a Lydia Street, Brunswick, Victoria 3056, Australia 15Department of Drug Management, Faculty of Health Sciences, Jagiellonian University Medical College, PL-31531 Krakow, Poland 16Department of Medical Biophysics, Faculty of Medicine in Hradec Králové, Charles University, 870 Simkova, CZ-50003 Hradec Králové, Czech Republic 17Istituto di Ricerche Farmacologiche ‘Mario Negri’ IRCCS, 2 Via Mario Negri, IT-20156 Milan, Italy 18Department of Pharmacy, Faculty of Medicine, University of Medicine, 28 Rr Isa Boletini, AL-1001 Tirana, Albania 19University of Medicine, 28 Rr Isa Boletini, AL-1001 Tirana, Albania20Dachverband der österreichischen Sozialversicherungen, 21 Kundmanngasse, AT-1030 Vienna, Austria 21Statistics Department, APB, 11 Rue Archimède, BE-1000 Brussels, Belgium 22Faculty of Pharmacy, Department of Social Pharmacy and Pharmacoeconomics, Medical University of Sofia, 2 Dunav Strasse, BG-1000 Sofia, Bulgaria 23State Agency of Medicines, 1 Nooruse, EE-50411 Tartu, Estonia 24IRDES, 117 bis rue Manin, FR-75019 Paris, France 25Pharmaceutical Drug Department, Azienda Sanitaria Locale di Verona, Azienda ULSS 9 Scaligera, 7 Via S D’Acquisto, IT-37122 Verona, Italy 26UBT – Higher Education Institut, A2 – Pharmaceutical Consulting, Nr 19, H18 Nurije Zeka, Mother Teresa Boulevard, 10000 Prishtina, Kosovo 27Medicines Marketing Authorisation Department, State Agency of Medicine, Riga, Latvia 28Department of Pharmacy, Ministry of Health of the Republic of Lithuania, 33 Vilniaus Gatve, LT-01506 Vilnius, Lithuania 29National Health Care Institute (ZIN), 4 Eekholt, NL-1112 XH Diemen, The Netherlands 30HTA Consulting, 17/3 Starowiślna Str, PL-31038 Cracow, Poland 31University of Banja Luka, Faculty of Medicine, Department of Social Pharmacy, 14 Save Mrkalja, Banja Luka, Republic of Srpska, Bosnia and Herzegovina 32Faculty of Medicine, Public Health and Management Department, “Carol Davila” University of Medicine and Pharmacy Bucharest, Room 224, et 2, 1-3 Dr Leonte Anastasievici Street, RO-050463 Bucharest, Romania 33ZEM Solutions, 9 Mosorska, RS-11000 Belgrade, 34Health Insurance Institute, 24 Miklosiceva, SI-1507 Ljubljana, Slovenia 35Faculty of Medicine, Slovak Medical University in Bratislava, 33 Gercenova, SL-85101 Bratislava, Slovakia 36Slovak Society for Pharmacoeconomics, 12 Budovatelska, SL-82108 Bratislava, Slovakia 37Drug Area, Catalan Health Service, 131 Travessera de les Corts, Edifici Olimpia, ES-08028 Barcelona, Spain 38Department of Pharmacology, Therapeutics and Toxicology, Universitat Autònoma de Barcelona, Plaça Cívica, Bellaterra, ES-08193 Barcelona, Spain 39Stockholm County Council, Health Care Management, Region Stockholm, 98 Lindhagensgatan, Box 6909, SE-10239 Stockholm, Sweden 40TLV (Dental and Pharmaceutical Benefits Agency), 18 Fleminggatan, SE-10422 Stockholm, Sweden. 41NHS National Services Scotland, Gyle Square, 1 South Gyle Crescent, Edinburgh, UK 42Canadian Organization for Rare Disorders, Suite 600, 151 Bloor Street West, Toronto, Ontario M5S 1S4, Canada 43Centre for Primary Care, Division of Population Health, Health Services Research and Primary Care, University of Manchester, Manchester M13 9PL, UK 44NIHR Greater Manchester Patient Safety Translational Research Centre, School of Health Sciences, University of Manchester, Manchester, UK 45Evidence Synthesis, Health Services Research, University of Liverpool, Liverpool, UK
References 1. OECD. Health at a Glance 2017 [homepage on the Internet]. [cited 2021 Jan 21]. Available from: https://www.oecd-ilibrary.org/social-issues-migration-health/health-at-a-glance-2017_health_glance-2017-en 2. Luzzatto L, Hyry HI, Schieppati A, Costa E, Simoens S, Schaefer F, et al. Outrageous prices of orphan drugs: a call for collaboration. Lancet. 2018;392(10149):791-4. 3. Prasad V, De Jesus K, Mailankody S. The high price of anticancer drugs: origins, implications, barriers, solutions. Nat Rev Clin Oncol. 2017;14(6):381-90. 4. Gyawali B, Sullivan R. Economics of cancer medicines: for whose benefit? New Bioeth. 2017;23(1):95-104. 5. Kelly RJ, Smith TJ. Delivering maximum clinical benefit at an affordable price: engaging stakeholders in cancer care. Lancet Oncol. 2014;15(3):e112-8. 6. Howard DH, Bach P, Berndt ER, Conti RM. Pricing in the market for anticancer drugs. J Econ Perspect. 2015;29(1):139-62. 7. Prasad V, Wang R, Afifi SH, Mailankody S. The rising price of cancer drugs – a new old problem? JAMA Oncol. 2017;3(2):277-8. 8. Memorial Sloan Kettering Cancer Centre. Price & value of cancer drug [homepage on the Internet]. [cited 2021 Jan 21]. Available from: https://www.mskcc.org/research-programs/health-policy-outcomes/cost-drugs 9. Bach PB, Saltz LB. Raising the dose and raising the cost: the case of pembrolizumab in lung cancer. J Natl Cancer Inst. 2017;109(11). 10. IMS Institute for Healthcare Informatics. Global oncology trend report. A review of 2015 and outlook to 2020. June 2016 [homepage on the Internet]. [cited 2021 Jan 21]. Available from: https://www.scribd.com/document/323179495/IMSH-Institute-Global-Oncology-Trend-2015-2020-Report 11. Godman B, Bucsics A, Vella Bonanno P, Oortwijn W, Rothe CC, Ferrario A, et al. Barriers for access to new medicines: searching for the balance between rising costs and limited budgets. Front Public Health. 2018;6:328. 12. Haycox A. Why cancer? PharmacoEconomics. 2016;34(7):625-7. 13. Godman B, Wild C, Haycox A. Patent expiry and costs for anti-cancer medicines for clinical use. Generics and Biosimilars Initiative Journal (GaBI Journal). 2017;6(3):105-6. doi: 10.5639/gabij.2017.0603.021 14. Simoens S, van Harten W, Lopes G, Vulto A, Meier K, Wilking N. What happens when the cost of cancer care becomes unsustainable. Eur Oncol Haemat. 2017;13(2):108-13. 15. Wilking N, Lopes G, Meier K, Simoens S, van Harten W, Vulto A. Can we continue to afford access to cancer treatment? Eur Oncol Haemat. 2017;13(2):114-9. 16. Waters R, Urquhart L. EvaluatePharma® World Preview 2019, Outlook to 2024. 2019. 17. Ghinea H, Kerridge I, Lipworth W. If we don’t talk about value, cancer drugs will become terminal for health systems. 2015. 18. European Commission. Communication from the commission to the European parliament, the council, the European economic and social committee and the committee of the regions. Pharmaceutical Strategy for Europe – {SWD(2020) 286 final}. November 2020 [homepage on the Internet]. [cited 2021 Jan 21]. Available from: https://eur-lex.europa.eu/legal-content/EN/TXT/PDF/?uri=CELEX:52020DC0761&from=EN 19. Bentley C, Costa S, Burgess MM, Regier D, McTaggart-Cowan H, Peacock SJ. Trade-offs, fairness, and funding for cancer drugs: key findings from a deliberative public engagement event in British Columbia, Canada. BMC Health Serv Res. 2018;18(1):339. 20. Wild C, Grossmann N, Bonanno PV, Bucsics A, Furst J, Garuoliene K, et al. Utilisation of the ESMO-MCBS in practice of HTA. Ann Oncol. 2016;27(11):2134-6. 21. World Health Organization. Access to new medicines in Europe: technical review of policy initiatives and opportunities for collaboration and research. 2015 [homepage on the Internet]. [cited 2021 Jan 21]. Available from: http://www.euro.who.int/__data/assets/pdf_file/0008/306179/Access-new-medicines-TR-PIO-collaboration-research.pdf?ua=1 22. World Health Organization. Pricing of cancer medicines and its impacts. 2018 [homepage on the Internet]. [cited 2021 Jan 21]. Available from: https://apps.who.int/iris/bitstream/handle/10665/277190/9789241515115-eng.pdf?sequence=1&isAllowed=y 23. Grössmann N, Del Paggio JC, Wolf S, Sullivan R, Booth CM, Rosian K, et al. Five years of EMA-approved systemic cancer therapies for solid tumours-a comparison of two thresholds for meaningful clinical benefit. Eur J Cancer. 2017;82:66-71. 24. Cohen D. Cancer drugs: high price, uncertain value. BMJ. 2017;359:j4543. 25. Suleman F, Low M, Moon S, Morgan SG. New business models for research and development with affordability requirements are needed to achieve fair pricing of medicines. BMJ. 2020;368:l4408-l. 26. AIM. Aim proposes to establish a European drug pricing model for fair and transparent prices for accessible pharmaceutical innovations. 2019 [homepage on the Internet]. [cited 2021 Jan 21]. Available from: https://www.aim-mutual.org/wp-content/uploads/2019/12/AIMs-proposal-for-fair-and-transparent-prices-for-pharmaceuticals.pdf 27. Uyl-de Groot CA, Löwenberg B. Sustainability and affordability of cancer drugs: a novel pricing model. Nat Rev Clin Oncol. 2018;15(7):405-6. 28. Hsu JC, Lin J-Y, Lin P-C, Lee Y-C. Comprehensive value assessment of drugs using a multi-criteria decision analysis: an example of targeted therapies for metastatic colorectal cancer treatment. PloS One. 2019;14(12):e0225938-e 29. Wilking N, Bucsics A, Kandolf Sekulovic L, Kobelt G, Laslop A, Makaroff L, et al. Achieving equal and timely access to innovative anticancer drugs in the European Union (EU): summary of a multidisciplinary CECOG-driven roundtable discussion with a focus on Eastern and South-Eastern EU countries. ESMO Open. 2019;4(6):e000550-e 30. Vogler S. Fair prices for medicines? Exploring competent authorities’ and public payers’ preferences on pharmaceutical policies. Empirica. 2019;46(3):443-69. 31. Moon S, Mariat S, Kamae I, Pedersen HB. Defining the concept of fair pricing for medicines. BMJ. 2020;368:l4726. 32. World Health Organization. WHO guideline on country pharmaceutical pricing policies, second edition. 2020 [homepage on the Internet]. [cited 2021 Jan 21]. Available from: https://apps.who.int/iris/bitstream/handle/10665/335692/9789240011878-eng.pdf 33. Sagonowsky E. AbbVie’s massive Humira discounts are stifling Netherlands biosimilars: report. 2019. Fierce Pharma. 2019 Apr 2. 34. Godman B, Hill A, Simoens S, Kurdi A, Gulbinovi J, Martin AP et al. Pricing of oral generic cancer medicines in 25 European countries; findings and implications. Generics and Biosimilars Initiative Journal (GaBI Journal). 2019;8(2):49-70. doi:10.5639/gabij.2019.0802.007 35. Hill A, Redd C, Gotham D, Erbacher I, Meldrum J, Harada R. Estimated generic prices of cancer medicines deemed cost-ineffective in England: a cost estimation analysis. BMJ Open. 2017;7(1):e011965. 36. Tefferi A, Kantarjian H, Rajkumar SV, Baker LH, Abkowitz JL, Adamson JW, et al. In support of a patient-driven initiative and petition to lower the high price of cancer drugs. Mayo Clin Proc. 2015;90(8):996-1000. 37. DeMartino PC, Miljkovic MD, Prasad V. Potential cost implications for all US Food and Drug Administration oncology drug approvals in 2018. JAMA Intern Med. 2020;e205921. 38. Vogler S, Schneider P, Zimmermann N. Evolution of average European medicine prices: implications for the methodology of external price referencing. Pharmacoecon Open. 2019;3(3):303-9. 39. Emanuel EJ, Zhang C, Glickman A, Gudbranson E, DiMagno SSP, Urwin JW. Drug reimbursement regulation in 6 peer countries. JAMA Intern Med. 2020. doi:10.1001/jamainternmed.2020.4793. 40. Vogler S, Zimmermann N, Babar ZU. Price comparison of high-cost originator medicines in European countries. Expert Rev Pharmacoecon Outcomes Res. 2017;17(2):221-30. 41. Vokinger KN, Hwang TJ, Grischott T, Reichert S, Tibau A, Rosemann T, et al. Prices and clinical benefit of cancer drugs in the USA and Europe: a cost–benefit analysis. Lancet Oncol. 2020;21(5):664-70. 42. Leopold C, Vogler S, Mantel-Teeuwisse AK, de Joncheere K, Leufkens HGM, Laing R. Differences in external price referencing in Europe: a descriptive overview. Health Policy. 2012;104(1):50-60. 43. Eatwell E, Swierczyna A. Emerging voluntary cooperation between European healthcare systems: are we facing a new future? Medicine Access@Point of Care. 2019;1-8. 44. O’Mahony JF. Beneluxa: what are the prospects for collective bargaining on pharmaceutical prices given diverse health technology assessment processes? Pharmacoeconomics. 2019;37(5):627-30. 45. European Commission. Defining value in “value based healthcare”. Report of the Expert Panel on effective ways of investing in Health (EXPH). 2019 [homepage on the Internet]. [cited 2021 Jan 21]. Available from: https://ec.europa.eu/health/sites/health/files/expert_panel/docs/024_defining-value-vbhc_en.pdf 46. Godman B, Wettermark B, van Woerkom M, Fraeyman J, Alvarez-Madrazo S, Berg C, et al. Multiple policies to enhance prescribing efficiency for established medicines in Europe with a particular focus on demand-side measures: findings and future implications. Front Pharmacol. 2014;5:106. 47. Moorkens E, Vulto AG, Huys I, Dylst P, Godman B, Keuerleber S, et al. Policies for biosimilar uptake in Europe: an overview. PloS One. 2017;12(12):e0190147. 48. Godman B, Malmström RE, Diogene E, Jayathissa S, McTaggart S, Cars T, et al. Dabigatran – a continuing exemplar case history demonstrating the need for comprehensive models to optimize the utilization of new drugs. Front Pharmacol. 2014;5:109. 49. Vogler S. The impact of pharmaceutical pricing and reimbursement policies on generics uptake: implementation of policy options on generics in 29 European countries–an overview. Generics and Biosimilar Journal (GaBI Journal). 2012;1(2):93-100. doi:10.5639/gabij.2012.0102.020 50. Ferrario A, Arāa D, Bochenek T, Ĉatić T, Dankó D, Dimitrova M, et al. The implementation of managed entry agreements in Central and Eastern Europe: findings and implications. Pharmacoeconomics. 2017;35(12):1271-85. 51. Vella Bonanno P, Bucsics A, Simoens S, Martin AP, Oortwijn W, Gulbinovic J, et al. Proposal for a regulation on health technology assessment in Europe – opinions of policy makers, payers and academics from the field of HTA. Expert Rev Pharmacoecon Outcomes Res. 2019;19(3):251-61. 52. Godman B, Shrank W, Andersen M, Berg C, Bishop I, Burkhardt T, et al. Policies to enhance prescribing efficiency in Europe: findings and future implications. Front Pharmacol. 2010;1:141. 53. Moon JC, Godman B, Petzold M, Alvarez-Madrazo S, Bennett K, Bishop I, et al. Different initiatives across Europe to enhance losartan utilization post generics: impact and implications. Front Pharmacol. 2014;5:219. 54. Vonĉna L, Strizrep T, Godman B, Bennie M, Bishop I, Campbell S, et al. Influence of demand-side measures to enhance renin-angiotensin prescribing efficiency in Europe: implications for the future. Expert Rev Pharmacoecon Outcomes Res. 2011;11(4):469-79. 55. Vogler S, Schneider P. Assessing data sources for medicine price studies. Int J Technol Assess Health Care. 2019;35(2):106-15. 56. Godman B, Petzold M, Bennett K, Bennie M, Bucsics A, Finlayson AE, et al. Can authorities appreciably enhance the prescribing of oral generic risperidone to conserve resources? Findings from across Europe and their implications. BMC Med. 2014;12:98. 57. Godman B, Shrank W, Andersen M, Berg C, Bishop I, Burkhardt T, et al. Comparing policies to enhance prescribing efficiency in Europe through increasing generic utilization: changes seen and global implications. Expert Rev Pharmacoecon Outcomes Res. 2010;10(6):707-22. 58. Godman B, Bishop I, Finlayson AE, Campbell S, Kwon HY, Bennie M. Reforms and initiatives in Scotland in recent years to encourage the prescribing of generic drugs, their influence and implications for other countries. Expert Rev Pharmacoecon Outcomes Res. 2013;13(4):469-82. 59. WHO Collaborating Centre for Drug Statistics Methodology. ATC/ DDD Index. 2019 [homepage on the Internet]. [cited 2021 Jan 21]. Available from: https://www.whocc.no/ 60. Adamski J, Godman B, Ofierska-Sujkowska G, Osinska B, Herholz H, Wendykowska K, et al. Risk sharing arrangements for pharmaceuticals: potential considerations and recommendations for European payers. BMC Health Serv Res. 2010;10:153. 61. Zampirolli Dias C, Godman B, Gargano LP, Azevedo PS, Garcia MM, Souza Cazarim M, et al. Integrative review of managed entry agreements: chances and limitations. Pharmacoeconomics. 2020;38(11):1165-85. 62. Pauwels K, Huys I, Vogler S, Casteels M, Simoens S. Managed entry agreements for oncology drugs: lessons from the European experience to inform the future. Front Pharmacol. 2017;8:171. 63. Darbà J, Ascanio M. The current performance-linked and risk sharing agreement scene in the Spanish region of Catalonia. Expert Rev Pharmacoecon Outcomes Res. 2019;19(6):743-8. 64. British pound to Euro spot exchange rates for 2013 from the Bank of England. Pound Sterling Live 2020. 65. British pound to Euro spot exchange rates for 2014 from the Bank of England. Pound Sterling Live 2020.. 66. British pound to Euro spot exchange rates for 2015 from the Bank of England. Pound Sterling Live 2020. 67. Sveriges Riksbank. Search interest & exchange rates [homepage on the Internet]. [cited 2021 Jan 21]. Available from: https://www.riksbank.se/en-gb/statistics/search-interest–exchange-rates/?g130-SEKEURPMI=on&from=28%2F12%2F2017&to=29%2F12%2F2017&f=Day&c=cAverage&s=Comma 68. Narodowy Bank Polski. Exchange rates [homepage on the Internet]. [cited 2021 Jan 21]. Available from: http://www.nbp.pl/homen.aspx?f=/kursy/kursyen.htm 69. National Bank of Serbia. Exchange rate [homepage on the Internet]. [cited 2021 Jan 21]. Available from: https://www.nbs.rs/export/sites/default/internet/english/scripts/kl_srednji.html 70. Norges Bank. Exchange rates [homepage on the Internet]. [cited 2021 Jan 21]. Available from: https://www.norges-bank.no/en/topics/Statistics/exchange_rates/ 71. Banca Naţionala a României. Exchange rates [homepage on the Internet]. [cited 2021 Jan 21]. Available from: https://www.bnr.ro/Exchange-Rates–3727.aspx 72. OECD Stat. Level of GDP per capita and productivity [homepage on the Internet]. [cited 2021 Jan 21]. Available from: https://stats.oecd.org/Index.aspx?DataSetCode=PDB_LV 73. European Central Bank. Euro foreign exchange reference rates. 1 July 2015 [homepage on the Internet]. [cited 2021 Jan 21]. Available from: https://www.ecb.europa.eu/stats/exchange/eurofxref/shared/pdf/2015/07/20150701.pdf 74. European Central Bank. Euro foreign exchange reference rates. 3 July 2017 [homepage on the Internet]. [cited 2021 Jan 21]. Available from: https://www.ecb.europa.eu/stats/exchange/eurofxref/shared/pdf/2017/07/20170703.pdf 75. Institute of Statistics. Population of Albania, 1 January 2017 [homepage on the Internet]. [cited 2021 Jan 21]. Available from: http://www.instat.gov.al/en/themes/demography-and-social-indicators/population/publication/2017/population-of-albania-1-januar-2017/ 76. World Population Data. Malta [homepage on the Internet]. [cited 2021 Jan 21]. Available from: http://worldpopulationreview.com/countries/malta-population/ 77. OECD Stat. Population data [homepage on the Internet]. [cited 2021 Jan 21]. Available from: https://stats.oecd.org/Index.aspx?DataSetCode=EDU_DEM 78. Republic of Cyprus demographic report, 2017 [homepage on the Internet]. [cited 2021 Jan 21]. Available from: https://www.mof.gov.cy/mof/cystat/statistics.nsf/All/6C25304C1E70C304C2257833003432B3/$file/demographic_report-2017-301118.pdf?OpenElement 79. Zamfir R. Romania is losing its people! Over 0.6 percent of the population vanished in just one year. Business Review. 2018 Aug 29. 80. Statistical Office of the Republic of Serbia. Estimates of population of the Republic of Serbia by sex, age and type of settlement 2013-2017. 2019 [homepage on the Internet]. [cited 2021 Jan 21]. Available from:http://publikacije.stat.gov.rs/G2018/PdfE/G201815012.pdf 81. The World Bank. Kosovo. 2019 [homepage on the Internet]. [cited 2021 Jan 21]. Available from: https://data.worldbank.org/country/kosovo 82. International Organization for Standardization (ISO). ISO 3166 Country Codes Alpha-3. 2013 [homepage on the Internet]. [cited 2021 Jan 21]. Available from: https://www.iso.org/obp/ui 83. R Core Team. R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. 2019 [homepage on the Internet]. [cited 2021 Jan 21]. Available from: https://www.R-project.org/ 84. Godman B, Kurdi A, McCabe H, Johnson CF, Barbui C, MacBride-Stewart S, et al. Ongoing initiatives within the Scottish National Health Service to affect the prescribing of selective serotonin reuptake inhibitors and their influence. J Comp Eff Res. 2019;8(7):535-47. 85. Simoens S. A review of generic medicine pricing in Europe. Generics and Biosimilar Journal (GaBI Journal). 2012;1(1):8-12. doi:10.5639/gabij.2012.0101.004 86. Godman B, Wettermark B, Bishop I, Burkhardt T, Fürst J, Garuoliene K, et al. European payer initiatives to reduce prescribing costs through use of generics. Generics and Biosimilars Initiative Journal (GaBI Journal). 2012;1(1):22-7. doi:10.5639/gabij.2012.0101.007 87. Godman B, Acurcio F, Guerra Junior AA, Alvarez-Madrazo S, Faridah Aryani MY, et al. Initiatives among authorities to improve the quality and efficiency of prescribing and the implications. J Pharma Care Health Sys. 2014;1(3):1-15. 88. McKee M, Stuckler D, Martin-Moreno JM. Protecting health in hard times. BMJ. 2010;341:c5308. 89. Markovic-Pekovic V, Skrbic R, Godman B, Gustafsson LL. Ongoing initiatives in the Republic of Srpska to enhance prescribing efficiency: influence and future directions. Expert Rev Pharmacoecon Outcomes Res. 2012;12(5):661-71. 90. Garuoliene K, Godman B, Gulbinovi J, Wettermark B, Haycox A. European countries with small populations can obtain low prices for drugs: Lithuania as a case history. Expert Rev Pharmacoecon Outcomes Res. 2011;11(3):343-9 91. Office of the Deputy Prime Minister and the Ministry for Health of Malta. Valletta Technical Group continues to grow. 2018 [homepage on the Internet]. [cited 2021 Jan 21]. Available from: http://www.livenewsmalta.com/index.php/2018/01/31/valletta-technical-group-continues-to-grow/ 92. O’Mahony JF. Beneluxa: what are the prospects for collective bargaining on pharmaceutical prices given diverse health technology assessment processes? Pharmacoeconomics. 2019;37(5):627-30. 93. Godman B, Wilcock M, Martin A, Bryson S, Baumgärtel C, Bochenek T, et al. Generic pregabalin; current situation and implications for health authorities, generics and biosimilars manufacturers in the future. Generics and Biosimilars Initiative Journal (GaBI Journal). 2015;4(3):125-35. doi:10.5639/gabij.2015.0403.028 94. Dylst P, Vulto A, Godman B, Simoens S. Generic medicines: solutions for a sustainable drug market? Appl Health Econ Health Policy. 2013;11(5):437-43. 95. Bochenek T, Abilova V, Alkan A, Asanin B, de Miguel Beriain I, Besovic Z, et al. Systemic measures and legislative and organizational frameworks aimed at preventing or mitigating drug shortages in 28 European and Western Asian Countries. Front Pharmacol. 2017;8:942. 96. Huang HY, Wu DW, Ma F, Liu ZL, Shi JF, Chen X, et al. Availability of anticancer biosimilars in 40 countries. Lancet Oncol. 2020;21(2):197-201. 97. Derbyshire M, Shina S. Patent expiry dates for biologicals: 2017 update. Generics and Biosimilars Initiative Journal (GaBI Journal). 2018;7(1):29-34. doi: 10.5639/gabij.2019.0801.003 98. Godman B, Allocati E, Moorkens E. Ever-changing landscape of biosimilars in Canada; findings and implications from a global perspective. Generics and Biosimilars Initiatives Journal (GaBI Journal). 2019;8(3):93-7. doi:10.5639/gabij.2019.0803.012 99. Hollis A. Sustainable financing of innovative therapies: a review of approaches. Pharmacoeconomics. 2016;34(10):971-80. 100. Jensen TB, Kim SC, Jimenez-Solem E, Bartels D, Christensen HR, Andersen JT. Shift from adalimumab originator to biosimilars in Denmark. JAMA Intern Med. 2020;180(6):902-3. 101. Godman B. Biosimilars are becoming indispensable in the management of multiple diseases although concerns still exist. Bangladesh Journal of Medical Science. 2021;20(1):5-10 102. Godman B, Allocati E, Moorkens E, Kwon H-Y. Can local policies on biosimilars optimize the use of freed resources – experiences from Italy. Generics and Biosimilars Initiative Journal (GaBI Journal). 2020;9(4):183-7. doi:10.5639/gabij.2020.0904.029 103. Moorkens M, Godman B, Huys I, Hoxha I, Malaj A, Keuerleber S, et al. The expiry of Humira® market exclusivity and the entry of adalimumab biosimilars in Europe: an overview of pricing and national policy measures. Front Pharmacol. 2021;11:591134. 104. NHS Scotland. Secondary care national therapeutic indicators 2019/20. 2019 [homepage on the Internet]. [cited 2021 Jan 21]. Available from:https://www.therapeutics.scot.nhs.uk/wp-content/uploads/2020/10/Secondary-care-NTIs-2019-20-final.pdf. 105. Lee SM, Jung JH, Suh D, Jung YS, Yoo SL, Kim DW, et al. Budget impact of switching to biosimilar trastuzumab (CT-P6) for the treatment of breast cancer and gastric cancer in 28 European countries. BioDrugs. 2019;33(4):423-36.
Author for correspondence: Brian Godman, BSc, PhD, Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, 161 Cathedral Street, Glasgow G4 0RE, UK
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Author byline as per print journal: Marzieh Zargaran1, PharmD, PhD Candidate; Abdol Majid Cheraghali 2,3, PharmD, PhD; Fatemeh Soleymani1,2, PharmD, MPH, PhD; Rajabali Daroudi4, BSc, MSc, PhD; Ali Akbari Sari4, MD, PhD; Professor Shekoufeh Nikfar1,2, PharmD, MPH, PhD
Background: Enacting national policies which empower the local production of medications is a promising way to improve the accessibility and affordability of medications, but this can also have unintended consequences. A number of such policies have been adopted by the Iranian government. This study was designed to examine the changes in the consumption of a number of selected pharmaceuticals which occurred in the years after these selected products began to be domestically produced. The implications of these changes were then evaluated for their potential to suggest possible policy changes. Methods: A 10-year trend study was conducted to identify changes which occurred between 2007 and 2017 in the consumption of 28 selected, imported medications after they began to be domestically produced. Results: Six different medication consumption patterns were observed after the development of domestic medication production. In addition, a downward trend in the cost of medications was observed, specifically due to the introduction of domestic pharmaceuticals. Discussion: Examination of the observed changes in the consumption patterns revealed that various factors affect consumption patterns of imported medications. Significant increases in certain domestically manufactured medications indicated that local production might result in the irrational use of medications. In addition, the competitiveness of Iranian products, in terms of quality and accessibility should be considered. Conclusion: New considerations are needed for health policymakers to support domestic production of viable alternative medications. However, increased accessibility of domestically produced medications may result in greater unreasonable use of medications.
Submitted: 28 February 2020; Revised: 29 December 2020; Accepted: 2 January 2021; Published online first: 15 January 2021
Introduction/Background
The domestic production of medications in developing countries can motivate and empower pharmaceutical industries and can enhance the accessibility of medications [1]. After the 1979 Islamic revolution in Iran, a comprehensive generic drug-based system was developed through the Iranian national drug policy (NDP), to promote affordable access to various types of medications [2]. To support the domestic production of generic medications and vaccines, the creation of a national pharmaceutical industry and national self-sufficiency in vaccine production were key aspects of the policy [3].
With 60 years’ experience in domestic medication production, the Iranian government has placed great emphasis on empowering the domestic pharmaceutical industry in recent decades [4, 5]. According to clause 28 of the health regulations laid out in the sixth Iranian development plan, at least 10% of National Development Fund resources have been deposited into domestic banks to promote the infrastructure of the health system, including that required for the production of pharmaceutical materials and products. In addition, to accomplish self-sufficiency of the pharmaceutical industry, clause 29 of the document obliges the Iranian Ministry of Health (MoH) to support and endorse domestic pharmaceutical plants.
A number of policies have been implemented to encourage Iranian pharmaceutical manufactures to develop their production capacity. High tariffs are imposed on imported medications, and in many cases imported medications are substituted with similar domestically produced alternatives present on the national reimbursement list (a list of medicinal products which are reimbursed through public health insurance), both of these policies reduce or prevent the import of certain foreign medications [2, 5].
Between 2010 and 2017, there was a significant increase (from 89 to 167) in the number of companies engaged in the production of pharmaceuticals in Iran. In addition, the number of companies importing pharmaceuticals during this time reduced from 207 to 93. There was also 1,213% growth in the price of the domestic pharmaceutical products between 1997 and 2010 [6]. However, it is noted that, despite the efforts of the Iranian government to support their national pharmaceutical industry, it is not yet comprehensively self-sufficient [2]. Due to the administration of the Health Sector Evolution Plan (HSEP) in 2014, and new approaches of MoH to support the national pharmaceutical industry, the annual pharmaceutical importation cost reduced from US$1 billion in 2013 to US$450 in 2014 [7].
Improvements in access to domestically produced pharmaceutical preparations can lead to additional changes in consumption patterns in some cases. The lower prices and greater affordability of domestically produced medications increases their availability and accessibility which can have some unintended consequences, such as their inappropriate and irrational consumption.
As such, comprehensive investigations on the management of national production and importation of pharmaceutical sciences are required. Identifying patterns of change in the consumption of medications associated with improvements in national pharmaceutical production will reveal future trends in the pharmaceutical market and help inform the decisions of policymakers.
This paper provides a 10-year overview of medication sales in terms of volume and value of imported medications after the development of domestic production lines in Iran. The main aim is to conduct a study to assess the trends in medication consumption after the initiation of domestic production. It also hopes to shed light on the unintended consequences of increased accessibility and affordability of medications brought about by increased domestic production, to help health policymakers in their future decision-making.
Finally, this review also aims to investigate the price of different selected medications.
Methods
Comprehensive literature review A literature review was conducted to determine the best methods to assess the trends associated with domestically produced medications and relevant policies. ISI/Web of Science, PubMed/MEDLINE, Scopus, Google Scholar, as well as Iranian databases such as Irandoc, Scientific Information Database (SID), Magiran and the grey literature, were used to find studies, both in English and Persian, that contained the following Medical Subject Headings (MeSH) keywords: local production, pharmaceutical market trends, pharmaceutical industry, health policy, and pharmaceutical policy. The publications found were not constrained to a specific time period.
Medication selection The method used to select the medications to be investigated was approved by Iranian Food and Drug Administration (IFDA) experts. This used data from Iranian pharmaceutical statistical datasheets which contain pharmaceutical sale statistics collected by IFDA from lists published annually by medication distribution companies. The sales volume and sales value of medications are reported in these data sheets and this is the most reliable data on medication consumption estimations in Iran. However, due to changes in IFDA policy, these datasheets are only available up to and including 2017. It is thought that new statistical datasheets will become available in the future.
In this study, pharmaceutical statistical datasheets between 2007 and 2017 were employed to find medications meeting the following requirements:
During the 10-year time period, they must have had a minimum of three years import history, followed by a minimum of two years of domestic Iranian production.
Figure 1 demonstrates the selection process and the sale history of 277 medications in the available statistical datasheets during the specified time period. For more than 80% of the medications, national pharmaceutical companies were able to domestically produce those which had been previously imported within three years of their introduction to the Iranian market. In addition, despite some medications being available in different strengths and dosage forms, each strength and dosage form of a particular medication were considered together.
The two-year period of domestic production was selected to ensure adequate follow up could be pursued and to ensure good comparisons between imported and domestic products could be made.
Consumption data collection Data from the IFDA pharmaceutical statistical datasheets on the annual sales volume and value of the medications identified for study, was investigated. Although, the sales volume and value of both imported and domestically produced medications were scrutinized separately, the overall consumption trend of each medication was also investigated. At this stage, 108 graphs were analysed to determine the exact pattern of changes within the selected time period.
Price data collection The price of pharmaceutical preparations is defined by the IFDA pricing committee and data on this is available on the IFDA website for free [8], however, the price of some preparations was not found which led to their exclusion from the study. In addition, due to the existence of various medication strengths, the price of each strength was separately reviewed. Thirteen medications were reviewed between 2014–2017 and the prices were calculated through converting Iranian Rials to USD in each respective year. Rial/USD conversion rate varied in successive years. All the exchange rates were obtained from the Central Bank of Iran, which was selected as the most reliable reference [9].
Inter-rate reliability was evaluated through checking the data by three members of the research team (for sales and price data) and the staff of IFDA (for price data).
Results
Literature review findings The findings of the literature review indicate that there is no applicable method to appraise the trends of domestic Iranian pharmaceutical production that is in accordance with IFDA policies frameworks.
Consumption data analysis During the 10-year period, only 28 of the 3,252 reviewed medications, that were either imported or domestically produced, were identified as eligible for inclusion in this study; having at least three years import history followed by a minimum of two years of domestic production. Considering all the strengths of each dosage form of the selected medications, a total of 57 preparations were scrutinized. The sales volume and value of these preparations in the respective years demonstrated various patterns of change in consumption of the imported medications after initiation of domestic production. Medications with similar changes in consumption pattern were categorized in separate groups.
Findings of this study revealed six patterns of change in consumption of the domestically produced medications which had been previously imported:
Pattern 1: Increased sales of domestically produced medications along with an elimination of imported products.
Pattern 2: Increased sales of domestically produced medications along with a reduction in the sales of imported products.
Pattern 3: Increased sales of both domestically produced and imported medications, with more domestically produced medications being sold (and consumed) than those that were imported.
Pattern 4: Increased sales of both domestically produced and imported medications, with more imported medications being sold (and consumed) than those that were domestically produced.
Pattern 5: Reduced sales of domestically produced medications along with an increase in the sales of imported products.
Pattern 6: Reduced sales of domestically produced medications along with a reduction in the sales of imported products.
Table 1 contains the 28 selected medications and their patterns of change during the time period of the investigation. The results show that medications of the same category can have various patterns of change.
According to IFDA reports, there was no unapproved importation, and all the imported medications were registered in the pharmaceutical statistical datasheets.
Price data analysis Thirteen medications were reviewed between 2010 and 2014. Documents showed that after 2014, the registered prices of the selected medications have fluctuated less than the previous years, and in most of the cases the prices in Rial did not vary. Given the annual reduction of the exchange rate in recent years with respect to the Iranian Rial and USD, the price of medications in USD exhibited a downward trend.
Figures 2 and 3 present the prices of the domestically produced and imported medications in USD.
Discussion
Background After resolution 61.21 of the World Health Assembly (WHA) was drawn up in 2008, many policies aiming to improve the domestic production of medications and to promote innovation and improvement in drug accessibility were designed in developing countries [10]. The aim of achieving self-sufficiency in pharmaceuticals production is considered one of the most important health system policies [11].
Recently, empowering domestic production of medications through policy implementation has also been occurring in low/middle income countries. The development of national pharmaceutical industries that produce generic drug products leads to lower prices, greater affordability and increased availability of medications [12]. This is seen in China, where domestic production of pharmaceutical products has been promoted through regulatory processes that are designed to facilitate the appraisal of new domestically produced medications [13]. Indian incentive policies have also dramatically affected the emergence of a successful pharmaceutical manufacturing sector. These include the establishment of Special Economic Zones (SEZs), modification of taxation system and price control [14]. In addition, developing countries have created some reforms to help implement self-sufficiency in pharmaceutical production, these include investment in developmental research and improvement of scientific capabilities [15].
The Iranian MoH has also adopted a domestic drug development approach to improve the availability and affordability of medications [16]. Since the implementation of HSEP in 2014, the Iranian government has supported the national production of medications through various strategies, such as imposing high tariffs on the imported medications, banning import of products similar to domestically produced preparations, supporting production of copy biopharmaceuticals produced by domestic industries, and substituting imported medications with similar domestically manufactured products present on the reimbursement lists [2, 5].
Medication consumption trends in Iran In this study, products consisting of ingredients produced domestically and those containing imported ingredients to make the finished product are classified as domestically produced medications. It is important to note that there is no documented report that outlines how much pharmaceutical importation pertains to the importation of active pharmaceutical ingredients (APIs), rather than finished products. As such, the ratio of imported active ingredient to imported finished product has been considered.
When it comes to follow-on biologicals, all steps of the production of follow-on biologicals occurs in Iran. Cell line and cell culture processing are the first steps of the manufacturing of follow-on biologicals and the approval of domestically produced follow-on biologicals requires comparative experiments, as well as preclinical and clinical studies. Proving the similarity of physicochemical and biological characteristics of a reference product and the domestically produced preparation, is one of the most important steps of the follow-on biologicals product approval pathway [8].
Vaccines are domestically produced in Iran; however, they were excluded from this study as they are not under supervision of IFDA
Although there is no appropriate method for evaluating the trends in domestic production in the Iranian context, the data collecting/selecting method of this study has been approved by IFDA experts. Based on the designed method, only 28 preparations met the required criteria for further analysis.
This is the first study to characterize medication consumption trends in Iran. Further complementary studies to evaluate the assumptions made in this study may be required.
Medication consumption patterns The findings of this study reveal various changes in the medication consumption patterns after the development of domestic production.
As shown in Table 1, medications classified in Patterns 1 and 2 were those with halted or reduced imports following the initiation of domestic production. Fourteen medications in different therapeutic categories exhibited these patterns, highlighting the domestically produced medications’ capability to reduce to the market share of imported medications.
However, the products that exhibit Pattern 3 indicate that in some cases, domestically produced medications fail to lower the market share of the imported products which leads to an increase in the total consumption rate of the medication regardless its origin (whether imported or domestically produced). The increase in the consumption rate of medications classified in Pattern 3 was rational in most cases. Here, non-communicable diseases have become more commonly diagnosed and treated in recent years, as such, related medications are also more commonly prescribed. Therefore, it is likely that increasing the total consumption rate now meets previously unmet demands.
In patterns 3 and 4 there is increased sales of domestically produced medications together with an increase in the sales of imported medications, however in Pattern 3 there are higher sales of domestically produced medications when compared to imported, and in Pattern 4 the sales of domestically produced medication are lower than imported. The difference between medications categorized in Patterns 3 and 4, is associated with the reduced market share of the imported medications following the domestic production of the medications in Pattern 4. However, the consumption of both imported and domestically manufactured medications significantly increased over the target years of the review.
Pattern 5 also addresses domestically produced medications which have failed to compete with imported products.
Only one of the selected medications belongs to Pattern 6, which indicates that despite the efforts of national industries to produce medications domestically, in some cases, reduction in the consumption rate occurred.
It is thought that determining the exact reasons that lead to the creation of the various medication consumption patterns can help Iranian health policymakers’ future decision-making. Understanding what lies behind the patterns will facilitate predicting the future path of other medications with similar charac-teristics.
These patterns demonstrate that the Iranian health system has been successfully supporting the domestic production of medications to increase accessibility and empower the domestic pharmaceutical industry. In 19 of the selected medications (67.8% of the medications), importation has been halted, reduced or increased (Pattern 3) after the empowering of national pharmaceutical industries which is indicative of the successful implementation of the policies supporting domestic production.
Sales value and volume of medications Figure 4 highlights that there is an observed reduction in the sales value proportion of imported medications when compared to those that are domestically produced. Regression equations of the sales value trend charts showed similar gradients of the sales value proportions of imported and domestically produced medications when compared to total medication consumption, both when increasing and decreasing.
According to the regression equations of the trend lines shown in Figure 5, since 2014, there has been an increase in the sales volume of domestically produced medications compared with the total medication consumption (of those included in the study).
Figures 6 and 7 show a significant increase in the sales value and sales volume consumption of certain domestically produced medications after the increased production of national products. For example, after three years of rosuvastatin tablet imports, the importation of this medication has been discontinued. Additionally, in the second year of domestic production, the annual average growth rate (AAGR) of the sales value and volume was approximately 3,160 % and 5,063 %, respectively, indicating a significant increase in both the sales volume and sales value of domestically produced rosuvastatin tablets.
In some cases, the evolution of the annual market in terms of the total sales of each medication did not correspond with, and was greater than, the respective year’s population growth. Here, Iranian health policymakers face great challenges when it comes to explaining the multi-fold consumption of certain medications following the initiation of domestic production. Increased consumption of medications is associated with the irrational use of these medications in approved indications and the unreasonable use in off-label and unapproved indications, which may occur due to lower prices or greater availability of domestically produced medications. Moreover, physicians are allowed to prescribe the medications for off-label indications in accordance with their diagnosis, however off-label use is not included in reimbursement in Iran.
Increasing the consumption rate of some medications could potentially meet previously unmet demands brought about due to a lack of access to medicines; this assumption can be confirmed through further investigation.
Medication price Of the 28 selected medicines with varieties of strength, only 13 medicines were reviewed in term of price, due to a lack of data on other medicines. The selection was not random or specific for a few medical classes. All the existing data on prices of medicine was reviewed.
Price analysis of the selected medications shows that since 2014, most of the selected domestically produced medications had a constant price in Rials. Due to the reduced exchange rate in recent years, domestic products have been presented at lower prices in USD. Comparisons of the trends in Figures 2 and 3 show that the price of the imported medications has increased more freely, therefore, importer companies experienced fewer price reductions when compared with manufacturers of the same products in Iran.
Based on the overall results of this investigation it is evident that, despite the government’s encouragement to support domestic manufacturers, in certain cases, domestically produced medications have failed to become viable competitors against imported products. According to Table 1, approximately 30% of the selected imported medications exceeded domestically produced medications in terms of volume over a period of at least two years.
Policy implications In general, the domestic production of pharmaceuticals can be evaluated from two perspectives. On one hand, for industrial stakeholders, increasing the market share through development of products is very important for domestic production. On the other hand, increasing accessibility of medications is the most important factor for health policymakers [17].
In many countries, the domestic production of pharmaceutical preparations may increase medication consumption and increase money spent on the pharmaceutical industry. Encouraging approaches that aim to increase domestic production in developing countries is in accordance with national pharmaceutical policy goals [6]. However, studies have not yet shown a clear and strong relationship between the domestic production of pharmaceuticals and increased accessibility of medications [18].
Empowering the pharmaceutical industry to enhance the availability and affordability of pharmaceutical products has been the focus of the Iranian government. Supporting domestic employment, self-sufficiency and saving money on the foreign exchange are among other objectives of the Iranian health sector authorities.
This study has demonstrated that insistence upon strengthening domestic production policies for improvements of medication accessibility might be in contrary to the NDP goals, leading to the irrational use of medications and an increased financial burden on the health system.
Another controversial challenge is the lack of a viable and permanent alternative for domestically produced medications. Despite the high cost of these medications, domestically manufactured medications may not always be a proper substitute for imported products. In these cases, discontinuing the import of similar products can lead to reduced accessibility of desirable and adequate medication.
It should be mentioned that all domestically produced medicines in Iran pass specific qualification examinations prior to market release and as such, there are no perceived differences in quality of medicines that could influence specific product selection. However, it is often seen that patients tend to opt for branded originator medications.
In addition, the Iranian government requires detailed policies to prioritize the medications requiring investments for national pharmaceutical industry advances. In other words, the most appropriate medications need to be selected for domestic production as sustainable substitutes for imported ones.
This study is the first investigation of the consumption trends of pharmaceuticals in Iran and addresses the challenges encountered by the health system policymakers. The findings of this study suggest that further challenges in developing countries by the health policymakers need to be discussed.
Study limitations The limitations of this study include the absence of similar research in this area due to the novelty of the topic, and inevitable errors in the data registration of statistical datasheets impacting on the outcomes of this study.
Pharmaceutical statistical datasheets based on distribution data are the only reliable references for estimating the sales of medications in Iran. Another important limitation of this research was that it assumed the medicine distribution data to be equal to medicine consumption or sales, although this may not be quite true. In addition, a lack of price data for some of the selected medications was the final limitation of this study.
Conclusion
From a health policy perspective, increasing domestic production of medications can have negative and unintended consequences. For example, increased accessibility following domestic production of medications may lead to greater unreasonable or irrational use of medications. Policymakers should be aware of such considerations and try to design reliable plans of medication selection for the domestic production of medications.
Acknowledgement
This research is part of a submitted doctoral dissertation in the faculty of pharmacy at Tehran University of Medical Sciences.
The authors are grateful to Dr Fatemeh Teymouri for her valuable assistance in some data collections.
The authors also thank Dr Marzieh Daniali for her ongoing collaboration in the English editing of this paper, and Ms Alice Rolandini Jensen, GaBI Journal editor, for English editing of the final version of this manuscript.
Competing interests: The authors have no conflicts of interest to declare.
Provenance and peer review: Not commissioned; externally peer reviewed
1Pharmacoeconomics and Pharmaceutical Administration Department, Faculty of Pharmacy, Tehran University of Medical Sciences, 16th Azar Street, Keshavarz Boulevard, 1417614411 Tehran, Iran 2Pharmaceutical Management and Economic Research Center, The Institute of Pharmaceutical Sciences (TIPS), Tehran University of Medical Sciences, Tehran, Iran 3Faculty of Pharmacy, BMS University, Tehran, Iran 4School of Public Health, Tehran University of Medical Sciences, Poorsina Avenue, Keshavarz Boulevard, 1417613151 Tehran, Iran
References 1. Kaplan W, Laing R. Health, Nutrition, and Population Family (HNP) of the World Bank’s Human Development Network (HNP Discussion Paper). Local production of pharmaceuticals: industrial policy and access to medicines. January 2005. 2. Nikfar S, Kebriaeezadeh A, Majdzadeh R, Abdollahi M. Monitoring of National Drug Policy (NDP) and its standardized indicators; conformity to decisions of the national drug selecting committee in Iran. BMC Int Health Hum Rights. 2005;5(1):5. doi:10.1186/1472-698x-5-5 3. Cheraghali AM, Nikfar S, Behmanesh Y, Rahimi V, Habibipour F, Tirdad R, et al. Evaluation of availability, accessibility and prescribing pattern of medicines in the Islamic Republic of Iran. East Mediterr Health J. 2004;10(3):406-15. 4. Lotfi K. Iran’s drug industry in the past 80 years (Part 1). Chem Dev. 2000;4:6-11. 5. Hashemi-Meshkini A. Making the public health and industrial objectives balanced; the big challenge of Iran’s Food and Drug Organization. Iran J Public Health. 2014;43(5):693-95. 6. Kebriaeezadeh A, Nassiri Koopaei N, Abdollahiasl A, Nikfar S, Mohamadi N. Trend analysis of the pharmaceutical market in Iran; 1997–2010; policy implications for developing countries. DARU J Pharm Sci. 2013;21(1):52. doi:10.1186/2008-2231-21-52 7. Dinarvand R. Significant reduction of drug imports to Iran with the implementation of the health system transformation plan. Government Information Database [homepage on the Internet]. [cited 2020 Dec 29]. Available from: http://dolat.ir/detail/288802. 8. Iran Food and Drug Administration [homepage on the Internet]. [cited 2020 Dec 29]. Available from: https://www.fda.gov.ir/en 9. Central Bank of Islamic Republic of Iran [homepage on the Internet]. [cited 2020 Dec 29]. Available from: https://www.cbi.ir 10. Sampath P, Mirza Z, Adachi K, et al. Local production for access to medical products: developing a framework to improve public health. World Health Organization. 2011. 11. United Nations Conference on Trade and Development. Local production of pharmaceuticals and related technology transfer in developing countries [homepage on the Internet]. [cited 2020 Dec 29]. Available from: https://unctad.org/system/files/official-document/diaepcb2011d7_en.pdf 12. World Health Organization. Local production and access to medicine in low- and middle-income countries. A literature review and critical analysis. 2011 [homepage on the Internet]. [cited 2020 Dec 29]. Available from: https://www.who.int/phi/publications/Local_Production_Literature_Review.pdf 13. World Health Organization. China policies to promote local production of pharmaceutical products and protect public health. 2017 [homepage on the Internet]. [cited 2020 Dec 29]. Available from: https://www.who.int/phi/publications/2081China020517.pdf?ua=1 14. World Health Organization. Indian policies to promote local production of pharmaceutical products and protect public health. 2017 [homepage on the Internet]. [cited 2020 Dec 29]. Available from: https://www.who.int/phi/publications/indian_policies_promote_local_production_pharm/en/ 15. Siagian R, Thabrany H. Reforms in pharmaceuticals self-sufficiency in developing countries. Indian J Sci Tech. 2019;12(11):1-7. 16. Cheraghali AM. Trends in Iran pharmaceutical market. Iran J Pharm Res. 2017;16(1):1-7. 17. Gebre-Mariam T, Tahir K, Gebre-Amanuel S. Bringing industrial and health policies closer: reviving pharmaceutical production in Ethiopia. In: Mackintosh M, Banda G, Tibandebage P, Wamae W, editors. Making medicines in Africa. International Political Economy Series. Palgrave Macmillan, London. 2016; p. 65-84. 18. Kaplan WA, Ritz LS, Vitello M. Local production of medical technologies and its effect on access in low and middle income countries: a systematic review of the literature. South Med Rev. 2011;4(2):51-61.
Author for correspondence: Professor Shekoufeh Nikfar, PharmD, MPH, PhD, Pharmacoeconomics and Pharmaceutical Administration Department, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
Disclosure of Conflict of Interest Statement is available upon request.
Permission granted to reproduce for personal and non-commercial use only. All other reproduction, copy or reprinting of all or part of any ‘Content’ found on this website is strictly prohibited without the prior consent of the publisher. Contact the publisher to obtain permission before redistributing.
Author byline as per print journal: Hye-Na Kang1, PhD; Robin Thorpe2, PhD; Ivana Knezevic1, PhD; Daehyun Baek3, PhD; Parichard Chirachanakul4; Hui Ming Chua5; Dina Dalili6, PhD; Freddie Foo7, MSc; Kai Gao8, PhD; Suna Habahbeh9, PhD; Hugo Hamel10, PhD; Edwin Nkansah11, PhD; Maria Savkina12, PhD; Oleh Semeniuk13; Shraddha Srivastava14; João Tavares Neto15, PhD; Meenu Wadhwa16, PhD; Teruhide Yamaguchi17, PhD
The World Health Organization (WHO) has provided specific guidance for biosimilar products to assist regulators, manufacturers and other professionals involved in the development and evaluation of these products. The development and approval of biosimilars are important for health care, as they allow the marketing of safe, efficacious and affordable biological products. Since the first biosimilars were approved in the EU in 2006, a series of biosimilars have been approved in many countries/geographical regions. This manuscript provides the figures on the status of approved biosimilars in 16 countries based on the information from regulatory experts and from publicly available data. It is clear that increasing numbers of biosimilars are now available in many countries and provide more options for treatments. It is expected that adoption of biosimilars will allow affordable health care and greater patient access to important medicinal products. It will also contribute to the overall WHO goal recognized by the World Health Assembly in 2014 by adopting a resolution on access to biotherapeutic products including biosimilars and on ensuring their quality, safety and efficacy.
Submitted: 12 October 2020; Revised: 25 November 2020; Accepted: 25 November 2020; Published online first: 14 December 2020
Introduction
Development of biosimilars is important for health care as it allows the marketing of safe, efficacious and affordable biological products. The European Medicines Agency (EMA) was the first regulatory agency to establish a process for the approval of biosimilars and approved the first biosimilars in 2006.
Since then, there has been much progress in establishing the regulatory pathway for biosimilars and a wide range of biosimilars have been approved for marketing in many countries/geographical regions [1]. An extensive number of biosimilars are now being used globally and are contributing considerably to widening patient access to appropriate biological medicines at reduced costs.
The World Health Organization (WHO) has taken a lead in the biosimilar field at the global level and has developed specific guidance for biosimilar development and approval as well as a number of other pertinent guidelines [2-4]. WHO has also organized a number of implementation workshops to assist regional regulatory agencies and manufacturers in the biosimilars area. As part of these workshops, surveys have been conducted to understand the current situation with biosimilars in the participants’ countries [1, 5, 6]. These surveys provide a unique opportunity to establish the situation with currently marketed biosimilars/similar biotherapeutic products in 16 countries. This publication presents this information.
Methods
The survey was conducted as previously described [1], but the information was updated and confirmed in July 2020. The information contained in this survey report is from participants of 15 countries who agreed for their information to be disclosed. The feedback from the UK refers to the situation in the European Union (EU) rather than specifically for the UK. Information from the US was not derived from the survey, but from the website of the US Food and Drug Administration (FDA). It should be noted that biological products in Table 1 have been approved as biosimilars in the countries as surveyed, but biosimilars approved in certain countries might not have been approved following a strict comparative regulatory process as recommended by WHO guidelines. The term ‘approval’ used in the manuscript is referring to the approval by the national regulatory authority. WHO did not conduct assessment of these products nor of the procedure for regulatory evaluation conducted by the national regulatory authorities as a basis for the ‘approval’.
Results
Table 1 shows a breakdown of information received which includes country participating (in survey), International Nonproprietary Name (INN), brand name and manufacturer/company name of product, the location of the producer of the product, the clinical indications approved, the reference product used and its manufacturer and the date the biosimilar/similar biotherapeutic products was approved. Table 2 shows the numbers of biosimilars/similar biotherapeutic products approved by regulatory authorities in the 16 countries (updated July 2020) specified by product type.
Discussion/Conclusions
Following the EU’s lead after their first biosimilar approvals in 2006, other countries have approved biosimilars/similar biotherapeutic products not only with increasing numbers but also with expanding the available product classes. ‘Big pharma’, e.g. in the EU and the US, continues to dominate the biosimilar market, but local manufacturers have played a significant role in producing biosimilars/similar biotherapeutic products in some countries, e.g. in China, India, Iran, Japan, Republic of Korea.
When compared with the situation in August 2019 [1], the major biosimilar products being approved as of July 2020 are monoclonal antibodies. For example, six and seven monoclonal antibody similar biotherapeutic products/biosimilars have been approved in Brazil and in Canada, respectively, during the updating period.
The quality of similar biotherapeutic products/biosimilars approved in some countries is still an issue for concern. Some products in certain countries were approved prior to adoption of regulations or guidelines for biosimilar evaluation, see Table 1. As mentioned above, EMA was the first agency to adopt the biosimilar concept in 2006, so products called ‘biosimilars’ approved before 2006 are unlikely to be biosimilars [1]. Regulators need to reassess such products to ensure whether they meet the current requirements and to identify the inappropriate labelling of non-innovator and copy-version products (approved when regulatory procedures were not well defined) as biosimilars [7-9].
It is clear that increasing numbers of biosimilars are now available in many countries and provide more options for treatments. In certain countries, the availability of various product classes has been expanded by approval of biosimilars for which product classes were not available on the market previously. This is important for relatively expensive products, e.g. monoclonal antibodies. It is expected that adoption of biosimilars will allow affordable health care and greater patient access to important medicinal products [1].
Disclaimer
The authors alone are responsible for the views expressed in this manuscript and they do not necessarily represent the views, decisions or policies of the institutions with which they are affiliated. The survey participants are listed in alphabetical order in the author section after the three primary authors.
The information in this manuscript provided based on the categorization of biosimilars by each national regulatory authority. Thus, biosimilars approved in certain countries might not have been approved following as strict a regulatory process as is required by WHO guidelines. Indications in Table 1 also as reported by survey participants; not necessarily representing WHO approval of these.
The World Health Organization retains copyright and all other rights (CC BY 3.0 IGO) in the manuscript of this article as submitted for publication.
Funding sources
The Ministry of Health and Welfare of Republic of Korea provided the fund to WHO for this project through a voluntary contribution for the period of 1 December 2018–30 September 2021.
Competing interests: The authors have disclosed no potential conflicts of interests.
Provenance and peer review: Not commissioned; externally peer reviewed.
Authors
Hye-Na Kang1, PhD Robin Thorpe2, PhD Ivana Knezevic1, PhD Daehyun Baek3, PhD Parichard Chirachanakul4 Hui Ming Chua5 Dina Dalili6, PhD Freddie Foo7, MSc Kai Gao8, PhD Suna Habahbeh9, PhD Hugo Hamel10, PhD Edwin Nkansah11, PhD Maria Savkina12, PhD Oleh Semeniuk13 Shraddha Srivastava14 João Tavares Neto15, PhD Meenu Wadhwa16, PhD Teruhide Yamaguchi17, PhD
1World Health Organization, Department of Health Product Policy and Standards, 20 Avenue Appia, CH-1211 Geneva, Switzerland 2Independent expert, Welwyn, UK 3Ministry of Food and Drug Safety, Osong, Republic of Korea 4Food and Drug Administration, Nonthaburi, Thailand 5National Pharmaceutical Regulatory Agency, Selangor, Malaysia 6Iran Food and Drug Administration, Tehran, Iran 7Health Sciences Authority, Singapore 8Shanghai University, Shanghai, People’s Republic of China 9Jordan Food and Drug Administration, Amman, Jordan 10Health Canada, Ottawa, Canada 11Food and Drugs Authority, Accra, Ghana 12Centre for Evaluation and Control of Medicinal Immunobiological Products of the FSBI «SCEEMP» of the Ministry of Health of Russia, Moscow, Russian Federation 13Ministry of Health of Ukraine, Kyiv, Ukraine 14Central Drug Standards Control Organization (CDSCO), Ministry of Health & Family Welfare, New Delhi, India 15Brazilian Health Regulatory Agency (ANVISA), Brasilia, Brazil 16National Institute for Biological Standards and Control, Medicines and Healthcare products Regulatory Agency, Potters Bar, UK 17Pharmaceuticals and Medical Devices Agency, Tokyo, Japan
References 1. Kang H-N, Thorpe R, Knezevic I, Survey participants from 19 countries. The regulatory landscape of biosimilars: WHO efforts and progress made from 2009 to 2019. Biologicals. 2020;65:1-9. 2. WHO Expert Committee on Biological Standardization. 2013. Annex 2. Guidelines on evaluation of similar biotherapeutic products (SBPs). WHO Technical Report Series no. 977 [homepage on the Internet]. [cited 2020 Nov 25]. Available from: http://who.int/biologicals/publications/trs/areas/biological_therapeutics/TRS_977_Annex_2.pdf 3. World Health Organization. WHO Questions and Answers: similar biotherapeutic products. 2018 [homepage on the Internet]. [cited 2020 Nov 25]. Available from: https://www.who.int/biologicals/expert_committee/QA_for_SBPs_ECBS_2018.pdf?ua=1 4. WHO Expert Committee on Biological Standardization. 2017. Annex 2. Guidelines on evaluation of monoclonal antibodies as similar biotherapeutic products (SBPs). WHO Technical Report Series no. 1004 [homepage on the Internet]. [cited 2020 Nov 25]. Available from: https://www.who.int/biologicals/biotherapeutics/WHO_TRS_1004_web_Annex_2.pdf?ua=1 5. Kang H-N. Summary of the diverse situation of similar biotherapeutic products in the selected countries (August 2010). Biologicals. 2011;39(5):304-7. 6. Kang H-N, Thorpe R, Knezevic I, Casa Levano M, Chilufya MB, Chirachanakul P, et al. 2020. Regulatory challenges with biosimilars: an update from 20 countries. Ann N Y Acad Sci. 2020 Nov 21. doi: 10.1111/nyas.14522. Online ahead of print. 7. Recommendations. 14th International Conference of Drug Regulatory Authorities (CDRA); 30 November–3 December 2010; Singapore. 8. Kang H-N, Knezevic I. Regulatory evaluation of biosimilars throughout their product life-cycle. Bull World Health Organ. 2018;96(4):281-5. 9. WHO Expert Committee on Biological Standardization. Annex 3. Regulatory assessment of approved rDNA-derived biotherapeutics. WHO Technical Report Series no. 999, 2016 [homepage on the Internet]. [cited 2020 Nov 25]. Available from: https://www.who.int/biologicals/areas/biological_therapeutics/Annex_3_Regulatory_assessment_of_approved_rDNA-derived_biotherapeutics.pdf?ua=1
Author for correspondence: Hye-Na Kang, PhD, World Health Organization, Department of Health Product Policy and Standards, 20 Avenue Appia, CH-1211 Geneva, Switzerland
Disclosure of Conflict of Interest Statement is available upon request.
Permission granted to reproduce for personal and non-commercial use only. All other reproduction, copy or reprinting of all or part of any ‘Content’ found on this website is strictly prohibited without the prior consent of the publisher. Contact the publisher to obtain permission before redistributing.
Author byline as per print journal: Kelly Canham1, BSc Hons; Claire Newcomb2, MSc
Introduction/Study Objectives: Etanercept is a tumour necrosis factor inhibitor indicated for the treatment of several inflammatory disorders. Patients with these diseases may experience manual dexterity challenges. Autoinjectors may improve dose accuracy, treatment adherence and quality of life; and reduce injection-site reactions. Studies have indicated patients prefer autoinjectors to other injection methods, however, patients must be able to demonstrate safe and effective use of an autoinjector for it to be a viable option. The YLB113 etanercept autoinjector may be a substitutable biosimilar to reference etanercept (Pfizer Manufacturing, Puurs, Belgium). This study sought to confirm intended users of the YLB113 etanercept autoinjector could demonstrate safe and effective use. Methods: The evaluation was performed among 79 participants representative of intended YLB113 etanercept autoinjector users; and included patients, caregivers and healthcare providers (HCPs). Results: All participants successfully delivered two simulated doses of etanercept into the foam pad using the autoinjector. Some participants experienced user errors, use difficulties, or close calls while simulating injection or answering knowledge questions. Discussion: In this usability evaluation, study patients, caregivers and HCPs demonstrated a high rate of injection success using the YLB113 etanercept autoinjector. Conclusions: The study results support demonstration of safe and effective use of the YLB113 etanercept autoinjector, a substitutable biosimilar to reference etanercept.
Submitted: 12 October 2020; Revised: 11 February 2021;Accepted: 15 February 2021; Published online first: 1 March 2021
Introduction/Study Objectives
Etanercept is a tumour necrosis factor inhibitor indicated for the treatment of rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, non-radiographic axial spondyloarthritis, and adult and paediatric psoriasis [1]. Patients suffering from the diseases for which etanercept is indicated may experience difficulties with manual dexterity that limit their ability to self-administer injections [2]. Autoinjectors (AIs) have been shown to offer several benefits to patients, including improved dose accuracy, ease of use, improved treatment adherence, and a reduced number of injection-site reactions [2]. In addition, studies suggest patients prefer AIs to other injection methods [3, 4]. However, for an AI to be a viable option, patients must be able to demonstrate safe and effective use [2]. Mylan, in collaboration with Lupin, is developing an etanercept AI, referred to here as the YLB113 etanercept AI, as a substitutable biosimilar product to Enbrel® (Pfizer Manufacturing, Puurs, Belgium) in the SureClick® AI. The etanercept solution is supplied in a single-use, disposable AI containing 50 mg/mL, as shown in Figure 1. Figure 2 shows a complete chronological task list for the injection process. In general, to administer a dose, the user must remove the needle cap and press the AI against the injection site. When the button is pressed, the AI clicks to indicate the start of the injection. A second click indicates the end of the injection. Following the second click, the AI must be held in place for an additional 15 seconds to ensure a full dose is delivered. After 15 seconds, the user can remove the AI from the skin and discard it in a sharps container.
The objective of this study was to confirm the intended users of the YLB113 etanercept AI could demonstrate safe and effective use through usability criteria predefined through risk assessment of the tasks. This is consistent with guidance from the European Union and United States regulatory authorities that, when needed, a human factors/usability study with the final version of the device should be completed to validate users’ performance with representative users in the environment of use [5-7].
Methods
The study was conducted in accordance with the principles of Good Clinical Practice and the provisions of the Declaration of Helsinki of 1964 and its later amendments. Participants eligible for study recruitment had the nature, purpose and risks of the study explained to them by the moderator. Informed consent was given by all participants and those aged younger than 18 years completed assent forms and were accompanied by a parent or guardian. Participants were provided a copy of the informed consent form for the study and were allowed time to consider whether they wanted to participate. Participant names were not included on the video, and all data were stored under protected computer systems that were only available to the usability vendor project team. The study protocol and supporting materials were reviewed and approved on 21 June 2019, by Core Human Factors, an independent Institutional Review Board located in Philadelphia, PA, USA, prior to collecting data from participants.
This summative usability evaluation study was performed among participants representative of intended YLB113 etanercept AI users that included patients, caregivers and healthcare providers (HCPs). Patients were included if they were diagnosed with a condition as described in the therapeutic indications section of the Enbrel summary of product characteristics [1] or, as few as possible children who had used any AI, e.g. epinephrine. Patients were divided into age groups of 12 to 17, 18 to 64, and 65 years and older. Caregivers (non-professionals) were included if they routinely helped someone ad-minister their medications. HCPs were included if they were a licensed nurse practitioner or registered nurse who administers or trains patients to administer medications using an AI, regardless of the patient diagnosis.
Intended YLB113 etanercept AI users may or may not have experience with AIs, therefore, half of the patient and caregiver groups were naïve to AI use and half had prior experience with AIs. Testing was conducted at multiple independent research facilities in the UK by a usability vendor. The study was conducted in a simulated home-use environment in which a moderator, following a script, interacted 1-on-1 (moderator to participant) or 1-on-2 (moderator to adolescent and their parent or guardian) to observe participants interacting with the user interface to simulate dose administration in accordance with a predefined task. The environmental conditions included standard room lighting, minimal noise distraction, and low-level background noise. The YLB113 etanercept AIs were presented in a carton representative of the shape and design of the commercial packaging. The labelling used in this study represented the Australian product as European labelling was still in development, see Figure 3 and Figure 4. The samples used in the study were not suitable for human injection and were intended only for simulated injection into a foam pad on the table. The foam pad had a hard plastic base to minimize the risk for accidental needle-stick injury. Supplies were presented to the participants or were available in the testing room for each session, and included a carton with four AIs, instructions for use, foam injection pad, hand sanitizer and paper towels, alcohol swabs, adhesive bandages, sharps bin, first aid kit, portable eye wash kit, and telephone. In addition, the testing room was equipped with cameras to enable a wide view of the moderator and participant, as well as a close-up view of the participant completing the task, to allow the project team to re-watch the session to aid in any root cause analysis.
As intended for all YLB113 etanercept AI users, participants received training on the usage of the commercially equivalent, single-use disposable AI according to a training guide one day before usability testing. A minimum of 18 hours with only one overnight between training and testing sessions was required to represent a reasonable time for knowledge decay from the time of receiving a prescription to administration of the first dose. During the testing session, participants were asked to simulate delivering a dose of medication into a foam pad twice in a row. Participants were given an opportunity to use the system independently and in as realistic a manner as possible, without guidance, coaching, or critique. Additional tasks and knowledge-based questions were used for further demonstration of safe and effective use. At the end of the task, a post-task interview was conducted to investigate the root cause of any use errors or close calls through open-ended questions and to record the participant’s perspective of their interaction with the user interface. In addition, a dynamometer was used to assess grip strength. The highest of three measurements from the dynamometer was taken from each participant and was averaged to calculate the mean maximum grip strength for each user group. A pinch gauge was also used to assess pinch strength. The highest of three measurements from the pinch gauge was taken from each participant and was averaged to calculate the mean maximum pinch strength for each user group.
Results
A total of 79 participants were included in this summative usability evaluation study. All the HCP participants in this study were female (n = 15). Across all other user groups, 63% were female. Demographic information, including gender, dominant hand, mean maximum grip strength, and mean maximum pinch strength are shown in Table 1.
The task and knowledge question outcome summary across all groups is shown in Table 2a and Table 2b. All (100%) participants successfully delivered both simulated doses from the YLB113 etanercept AI into the foam pad and answered knowledge questions on where to store the pens, what the liquid should look like, where to look to see the liquid, injecting at 90°, initiating the injection, removing the pen from the injection site, and performing the injection without injury. Some participants experienced use errors, use difficulties, or close calls while performing tasks or answering knowledge questions. Success was recorded when no use errors, usability issues, close calls, or issues necessitating assistance were observed, see Table 3. Success rates for the tasks and knowledge questions were: removing the pen from carton (92%), knowing to let the pen reach room temperature (97%), reporting the expiry date (99%), knowing when a full dose has been taken (99%), washing their hands (94%), knowing the correct injection site (97%), cleaning the injection site (99%), removing the safety cap (96%), disposing of the cap in a sharps container (98%), stretching the skin (88%), holding the AI down for 15 seconds after the second click (98%), and disposing of the pen in the sharps container (96%). A total of 11 use errors occurred on critical tasks over 158 simulated injections. The root cause analyses of these use errors are shown in Table 4. Use difficulties only occurred when removing the pen from the carton (n = 11) and stretching the skin at the injection site (n = 1)
Discussion
In this summative usability evaluation study conducted at multiple independent research facilities in the United Kingdom, patients across all age groups, caregivers, and HCPs demonstrated a high rate of injection success using the YLB113 etanercept AI. All participants were able to successfully deliver two simulated injections into a foam pad, including patients and caregivers with or without prior AI experience. In addition, all participants indicated they knew where to store the pens, what the liquid should look like, and where to look to see the liquid. All participants also demonstrated success with injecting at 90°, initiating the injection, removing the pen from the site, and performing the injection without injury. Although the vast majority of participants demonstrated success across all other success criteria, some participants experienced use errors, use difficulties, or close calls while performing tasks or answering knowledge questions, see Table 4.
Limitations
A limitation of this study is that injections were simulated into a foam pad at a research facility as opposed to using the AI in a clinical or home-use setting. However, it is important to note that simulated-use testing, as employed in this study, is sufficient to assess the adequacy of the user interface for most combination products, according to health authority guidance [5-7]. In addition, it is anticipated that patients being prescribed the YLB113 etanercept AI will receive training, however, the training of all participants prior to simulating an injection limits the generalizability of these findings to those who have not received such training.
Conclusions
Patients across all age ranges, grips strengths, and pinch strengths; caregivers and HCPs were able to successfully deliver two doses of etanercept into a foam pad to demonstrate safe and effective use of the AI. The results from this study support the demonstration of safe and effective use of the YLB113 etanercept AI as a substitutable biosimilar product to Enbrel.
For patients
Antitumour necrosis factor inhibitors, such as etanercept, are indicated for use in patients suffering from inflammatory conditions in the form of rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, axial spondyloarthritis, and adult and paediatric psoriasis. Patients suffering from these conditions may receive benefits from the use of self-administered injectable medications, such as improved compliance, ease of use, dosing accuracy, and fewer injection-site reactions. Research indicates patients prefer autoinjectors (AI) to traditional injections, however, inflammatory diseases commonly present with clinical manifestations that limit dexterity and ability to manoeuvre AI devices. The YLB113 etanercept AI may be a substitutable biosimilar product to Enbrel®, and this manuscript reviews the summative usability studies of YLB113 etanercept AI among intended users. The findings confirm that intended users across all age ranges, and grip and pinch strengths, including patients, caregivers and healthcare professionals, were able to demonstrate safe and effective use of the device. The results from this study support the demonstration of safe and effective use of the YLB113 etanercept AI as a biosimilar substitute product to Enbrel®.
Declarations
Compliance with ethics guidelines
The study was conducted in accordance with the principles of Good Clinical Practice and the provisions of the Declaration of Helsinki of 1964 and its later amendments. Participants eligible for study recruitment had the nature, purpose, and risks of the study explained to them by the moderator. Informed consent was given by all participants and those aged younger than 18 years completed assent forms and were accompanied by a parent or guardian. Participants were provided a copy of the informed consent form for the study and were allowed time to consider whether they wanted to participate. Participant names were not included on the video, and all data were stored under protected computer systems that were only available to the usability vendor project team. The study protocol and supporting materials were reviewed and approved on 21 June 2019 by Core Human Factors, an independent Institutional Review Board located in Philadelphia, PA (USA), prior to collecting data from participants.
Author contributions
All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this manuscript, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published. The authors made all content and editorial decisions and received no financial support or other form of compensation related to the development of this manuscript. All authors had final approval of the manuscript and are accountable for all aspects of the work in ensuring the accuracy and integrity of this manuscript. Authors have full control of all primary data and agree to allow the journal to review the data if requested.
Competing interests: KC and CN are employee and shareholder of Mylan.
Provenance and peer review: Not commissioned; externally peer reviewed.
Authors
Kelly Canham1, BSc Hons Senior Device Development Manager and Human Factors Lead Claire Newcomb2, MSc
1Viatris/Mylan Pharma UK Ltd (formerly Mylan Pharma UK Ltd), Suite 13 Science Village, Chesterford Research Park, Cambridge CB10 1XL, UK 2Viatris/Mylan Pharma UK Ltd (formerly Mylan Pharma UK Ltd), Floor 3, Discovery Park House, Discovery Park, Ramsgate Road, Sandwich, Kent CT13 9ND, UK
References 1. Enbrel® (INN-etanercept) [summary of product characteristics]. Puurs, Belgium: Pfizer Manufacturing; 2019. 2. Weinhold T, Del Zotto M, Rochat J, Schiro J, Pelayo S, Marcilly R. Improving the safety of disposable auto-injection devices: a systematic review of use errors. AAPS Open. 2018;4:7. 3. Vermeire S, D’heygere F, Nakad A, Franchimont D, Fontaine F, Louis E, et al. Preference for a prefilled syringe or an auto-injection device for delivering golimumab in patients with moderate-to-severe ulcerative colitis: a randomized crossover study. Patient Prefer Adherence. 2018;12:1193-202. 4. Gandell DL, Bienen EJ, Gudeman J. Mode of injection and treatment adherence: results of a survey characterizing the perspectives of health care providers and US women 18-45 years old. Patient Prefer Adherence. 2019;13:351-61. 5. EN 62366:2015 Medical devices – Part 1: Application of usability engineering to medical devices. 6. Medical & Healthcare Products Regulatory Agency. Human factors and usability engineering – Guidance for medical devices including drug-device combination products. 2021 [homepage on the Internet]. [cited 2021 Feb 11]. Available from: https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/645862/HumanFactors_Medical-Devices_v1.0.pdf 7. U.S. Food and Drug Administration. Human factors studies and related clinical study considerations in combination product design and development. Draft guidance for industry and FDA staff. 2016. [homepage on the Internet]. [cited 2021 Feb 11]. Available from: https://www.fda.gov/media/96018/download
Author for correspondence: Kelly Canham, BSc Hons, Senior Device Development Manager and Human Factors Lead, Viatris/Mylan Pharma UK Ltd (formerly Mylan Pharma UK Ltd), Suite 13 Science Village, Chesterford Research Park, Cambridge CB10 1XL, UK
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Author byline as per print journal: Jolita Seckute1, PhD; Ingrid Castellanos2, PhD; Steven Bane1, PhD
Study Objectives: To evaluate extended in-use stability of bevacizumab biosimilar, ABP 215, after dilution into intravenous bags, extended storage, and simulated infusion to enable advanced preparation and storage. Methods: Two lots of ABP 215 were diluted to high- (16.5 mg/mL) and low- (1.4 mg/mL) dose concentrations in two types of intravenous bag under ambient light conditions. Dosed intravenous bags were stored at 2°C–8°C for 35 days, followed by 30°C for 2 days, and each bag was infused on Day 37. Analysis of purity and physicochemical stability was performed using size-exclusion high-performance liquid chromatography (SE-HPLC), cation-exchange high-performance liquid chromatography (CEX-HPLC), reduced capillary electrophoresis-sodium dodecyl sulphate (rCE-SDS), subvisible particle detection assays, visual inspection, and by measuring protein concentration and potency. Results: No meaningful changes were seen in ABP 215 purity when analysed by SE-HPLC, CEX-HPLC and rCE-SDS following dilution, storage and infusion of two lots, bags, and doses. Protein concentration remained consistent throughout the study for all samples and no significant loss in potency was detected. No potentially proteinaceous particles or increases in subvisible particles were observed. Discussion: This study investigated the in-use stability of ABP 215 following dilution, extended storage, and infusion, that represent worst-case handling conditions. ABP 215 exhibited consistent product quality and activity, with no significant degradation observed under the conditions tested. Conclusion: ABP 215 retains physicochemical stability after dilution over the recommended dosing concentrations, extended storage, and simulated infusion. This supports the advance preparation and storage of ABP 215 in intravenous bags for infusion.
Submitted: 28 July 2020; Revised: 25 September 2020;Accepted: 28 September 2020; Published online first: 12 October 2020
Introduction/Study objectives
Bevacizumab (Avastin®) is a humanized monoclonal antibody targeting vascular endothelial growth factor A (VEGF-A) [1]. It binds to VEGF-A, preventing it from interacting with endothelial cell surface receptors, thus affecting the formation of new blood vessels and endothelial cell proliferation [1]. Bevacizumab was approved in the US in 2004 [2], and EU in 2005 [3] for the treatment of a variety of advanced solid tumours including: colorectal cancer, non-small cell lung cancer (NSCLC), renal cell cancer, epithelial ovarian, fallopian tube or primary peritoneal cancer, cervical cancer, recurrent glioblastoma (US only), and breast cancer (EU only) [4, 5].
ABP 215 (MVASITM), a bevacizumab biosimilar, was licensed for use in the US in September 2017 and was the first approved biosimilar to bevacizumab [6, 7]. Subsequently, approval was granted for use of ABP 215 in the EU in January 2018 [8]. ABP 215 is approved in combination with other agents for the treatment of metastatic colorectal cancer; unresectable, locally advanced, recurrent or metastatic non-squamous NSCLC; metastatic renal cell carcinoma; and persistent, recurrent, or metastatic cervical cancer [9, 10]. Similar to reference bevacizumab, ABP 215 is also approved in the US for the treatment of recurrent glioblastoma [9]. In the EU, it has additional indications, in combination with chemotherapy, for metastatic breast cancer; advanced or recurrent epithelial ovarian, fallopian tube and primary peritoneal cancer; and unresectable, advanced, recurrent or metastatic NSCLC other than that of predominantly squamous cell histology [10].
The structural and functional similarity, including, for example, primary and higher order structure, biological activity and thermal forced degradation of ABP 215 compared with reference bevacizumab (from both US and EU sources), have previously been demonstrated [11]. The pharmacokinetic (PK) profile of ABP 215 and bevacizumab were initially demonstrated to be similar during phase I clinical studies performed in healthy males [12, 13]. The clinical efficacy, safety, PKs and immunogenicity of ABP 215 and bevacizumab were subsequently confirmed to be similar in a phase III study in patients with advanced NSCLC [14].
ABP 215 is supplied commercially as a liquid drug product in single-use vials at a concentration of 25 mg/mL. It is administered by intravenous (IV) infusion after dilution in a pre-filled infusion bag. The administered dose of ABP 215 is weight-based and ranges from 5 mg/kg to 15 mg/kg, depending on the indication [9, 10]. The recommended final IV bag concentration range is 1.4 mg/mL to 16.5 mg/mL [10].
In Europe and other regions, IV bags may be routinely prepared at centralized hospital pharmacy locations using aseptic techniques and then distributed to clinical oncology sites for patient administration. The practice of dose banding allows for the advance preparation of specific doses of drugs with sufficient stability [15, 16]. Standardization of chemotherapy doses through dose banding has been shown to decrease drug spending [17] and improve overall safety in drug ordering [18]. Other potential benefits include a reduction in medication preparation errors, patient waiting times and drug wastage [19]. Dose banding of bevacizumab currently takes place in hospital pharmacies in Europe [20, 21] and the US [18]. Extended physicochemical stability of ABP 215 under in-use conditions would enable flexibility in administration, by ensuring efficacy during handling conditions not covered by the standard stability studies performed previously [11].
Here we evaluate the extended storage (at 2°C–8°C for 35 days and then at 30°C for 48 hours) and simulated infusion of ABP 215 in IV bags. The extended in-use chemical and physical stability of ABP 215 in IV bags was evaluated for two different drug product lots, diluted at two different protein concentrations.
Methods
IV bag preparation and sample collection
Two different IV bag models were used in the study, B Braun partial additive bag (PAB) S8004-5264 (polyolefin, free of latex, polyvinyl chloride (PVC) and DEHP (bis[2-ethylhexyl] phthalate)) and Baxter Viaflex bag 2B1302 (PVC), and are referred to throughout as PAB and PVC, respectively, see Figure 1. The PAB bags are used pre-filled and contain 109 ± 4 mL of saline (0.9% sodium chloride) at pH 5.5; the PVC bags are used pre-filled and contain 110 ± 5 mL of saline (0.9% sodium chloride) at pH 5. ABP 215 is supplied at a concentration of 25 mg/mL in 51 mM sodium phosphate, 60 mg/mL α, α-trehalose dihydrate, 0.040% w/v polysorbate 20 at pH 6.2. Two drug product lots were tested in this study, with both lots being approximately 18 months old at study end, see Figure 1.
ABP 215 was diluted into 100 mL saline IV bags, which resulted in the final concentration targets of 1.4 mg/mL (low dose) and 16.5 mg/mL (high dose), for both drug product lots. An additional study arm IV bag was prepared containing ABP 215 formulation buffer (preparation simulated the high-dose bag dosing) and was used as a control for the visual inspection and high-accuracy light obscuration (HIAC) analyses.
The prepared IV bags were stored at 2°C–8°C for 35 days, followed by storage at 30°C for 2 days (to represent the worst-case storage conditions at the patient administration site). IV infusion was simulated for each bag on Day 37. Infusion was set to simulate a nominal 100 mL bag volume infusion over 90 minutes (the slowest recommended clinical infusion duration for the worst-case product contact assessment within the infusion system), with a resulting infusion rate of 67 mL/hour. The infused contents were collected in a sterile polyethylene terephthalate copolyester, glycol modified bottle. Preparation of the IV bags, sampling throughout the study, and infusion took place at facility room temperature under ambient light conditions, in line with clinical practice.
Samples were collected at the following timepoints, see Figure 1: T = 0, after IV bag dosing (at facility room temperature), Days 14, 30 and 35 (during storage at 2°C–8°C), Days 36 and 37 (during storage at 30°C), and T = final (Day 37) after infusion (at facility room temperature). The samples collected on Days 14 and 30 (2°C–8°C) and Day 36 (30°C) were retention samples for size-exclusion high-performance liquid chromatography (SE-HPLC), cation-exchange high-performance liquid chromatography (CEX-HPLC), reduced capillary electrophoresis-sodium dodecyl sulphate (rCE-SDS) and potency analysis, and were collected for testing only if required to assess observed potential trends. Due to the inherent variability of HIAC data, this assay was performed on Day 14 as an additional confirmatory data point for each study arm. In general, samples were collected into cryo vials and frozen prior to analysis, with visual inspection and HIAC samples collected into 20 cc clear glass vials and analysed on the same day.
Assessment of physical and chemical stability of ABP 215
The following were methods chosen to assess ABP 215 as they are indicative of drug product stability and pharmaceutical quality. The purity assays, potency and subvisible particle testing are sensitive to higher order structure changes, conformational changes, biological activity and aggregation.
Purity
SE-HPLC was used to evaluate the size heterogeneity of native or non-denatured ABP 215. SE-HPLC measurements were made on an Agilent HPLC system using a Tosoh Bioscience TSK-GEL G3000SWXL column. Briefly, 300 µg of each sample was injected onto the column and eluted isocratically over 35 minutes with 100 mM sodium phosphate, 250 mM sodium chloride, pH 6.8, with a flow rate of 0.5 mL/min using an HPLC system running Empower software. Ultraviolet (UV) absorbance at 280 nm was used to monitor the analytes. The peak area of each species was determined as a percentage of the total peak area to evaluate the purity of the sample [11]. During the study, high molecular weight (HMW) species were resolved from the main peak.
CEX-HPLC was used to assess the charge heterogeneity of ABP 215. Charged variants within the ABP 215 samples were separated on a Dionex ProPac WCX-10 analytical column using a Waters HPLC system. Briefly, 50 µg of each sample was injected onto the column and eluted with a gradient from 20 mM sodium phosphate, pH 6.3 to 20 mM sodium phosphate, 500 M sodium chloride, pH 6.3 using an HPLC system running Empower software. Fractions were eluted using a salt gradient and monitored by UV absorbance at 280 nm. To evaluate purity of the sample, the peak area of each separately eluting charge variant group (main, basic and acidic peaks) was determined as a percentage of the total peak area [11].
The relative amount of size variants based on protein hydrodynamic size, including heavy chain (HC) and light chain (LC) variants, was assessed using rCE-SDS, an orthogonal molecular sizing method. Denatured protein size variants were separated under reduced conditions. SDS and β-mercaptoethanol (reduction buffer) were used to denature and reduce samples of ABP 215, respectively. Samples were incubated in the reducing buffer at 70°C for 10 minutes. Denatured samples were then injected onto a 57 cm, 50 µm internal diameter Beckman Coulter bare, fused silica capillary. An electric field was applied using a Beckman Coulter capillary electrophoresis system, which resulted in the separation of samples based on hydrodynamic size, with the time taken to migrate for smaller size proteins inversely related to their overall size. UV absorbance at 220 nm was used to monitor analytes, and the purity of the sample was evaluated by determining the peak area of each species as a percentage of the total peak area [11].
Protein concentration and recovery
The amount of protein loss due to surface contact binding was assessed by measuring the protein concentration. The protein concentration in the solution was determined by UV absorbance using variable pathlength technology [11]. Protein recovery was calculated as the ratio of the final 37-day post-infusion (T = final) protein concentration over the initial time 0 (T = 0) measurement and was expressed as a percentage.
Potency
The biological activity of ABP 215 was evaluated using a quantitative, cell-based proliferation inhibition bioassay. The dose-dependent inhibitory effects of ABP 215 on the proliferation of vascular endothelial growth factor receptor-expressing human umbilical vein endothelial cells (HUVEC) were measured. HUVEC express both VEGF-R1 and VEGF-R2 receptors, which interact with and bind VEGF resulting in endothelial cell proliferation. HUVEC were incubated with a constant concentration of VEGF and varying concentrations of ABP 215 reference standard, control and test samples. Following a timed incubation, an adenosine triphosphate (ATP)-specific luminescent reagent was added to the assay plates, resulting in cell lysis and generation of luminescence signal that was proportional to the amount of ATP present. The quantity of ATP was directly proportional to the number of viable cells and inversely proportional to the ABP 215 concentration in tested samples. The sample response relative to the reference standard was determined using a 4-parameter logistic model fit. Results are reportable by meeting assay acceptance criteria and sample acceptance criteria for parallelism between test samples and the reference standard curve. Results were reported as per cent relative potency values [11].
Visual inspection and subvisible particle count
The presence and any trends in potentially proteinaceous particles were evaluated by visual inspection, and HIAC was used to assess subvisible particle trends. A HIAC liquid particle counting system (HACH 9703+) equipped with a light obscuration sensor was used to assess the presence of subvisible particles [11]. The average and standard deviation of the subvisible particles in the ³ 10 μm and ³ 25 μm range were determined. Results were reported as the average of three measurements with the standard deviation indicated on the graph for each result.
Results
Purity
For all three purity assays (SE-HPLC, CEX-HPLC and rCE-SDS), no meaningful changes were seen. SE-HPLC analysis of low- and high-dose ABP 215 from both lots and types of IV bag demonstrated that the percentage of main peak ranged between 97.4% and 98.1%. The HMW peak values for all lots, bags and doses ranged between 1.8% and 2.5%. For SE-HPLC, there were lower levels of HMW species in the low-dose samples compared with the highdose samples, with corresponding changes seen in the main peak, see Figure 2. The main peak results from the CEX-HPLC analysis of low- and high-dose ABP 215 from both lots and types of IV bag ranged between 66.9% and 70.4%. The acidic and basic peak results for both doses and lots in each IV bag model, ranged between 19.8% and 23.9%, and 8.6% and 11.3%, respectively, see Figure 3. On rCE-SDS, the percentage of heavy chain and light chain in all samples ranged between 97.4% and 98.0%, see Figure 4.
Protein concentration and recovery
No meaningful changes were observed in protein concentration for either ABP 215 lots or doses throughout the duration of exposure to the IV bags and infusion system materials, see Figure 5. For the low and high doses, ABP 215 concentrations ranged from 1.3 mg/mL to 1.4 mg/mL, and 16.0 mg/mL to 16.4 mg/mL, respectively. Across samples, protein recovery ranged from 99.4% to 101.7%.
Potency
In the proliferation inhibition assay, there were no practically significant losses in potency over the study duration, see Figure 6. The tested samples had relative potencies between 83% and 120%.
Visual inspection and subvisible particle count
Throughout the study no potentially proteinaceous particles were observed by visual inspection. For both types of IV bag, both ABP 215 doses and lots, and the control formulation buffer samples, there were no consistent trends over time seen in the subvisible particle analysis, see Appendix Figure 1. In the ABP 215 samples, particle counts/mL ranged between 9 and 64 for particles ³ 10 µm, and between 0 and 4 for particles ³ 25 µm.
Discussion
This study investigated the in-use stability of ABP 215, a bevacizumab biosimilar, after dilution into two types of IV bag. This type of study builds on the standard stability studies conducted to fulfil regulatory licensing requirements and more closely reflects the conditions encountered in a realworld, hospital pharmacy setting.
The effect of extended storage and simulated infusion on the physical and chemical stability of ABP 215 was assessed for two separate ABP 215 lots, diluted to two different protein concentrations. The high (16.5 mg/mL) and low (1.4 mg/mL) ABP 215 doses used here represent the concentration limits used in clinical practice. The IV bags containing ABP 215 were prepared in ambient light conditions, stored at 2°C–8°C for 35 days and 30°C for an additional 2 days, and finally infused over 90 minutes, at an infusion rate of 67 mL/hour. This is the slowest recommended infusion rate, thereby providing worst-case duration of product contact with the infusion system. Under these dilution, storage and infusion conditions, including worst-case handling conditions, ABP 215 demonstrated consistent product quality and activity across a robust set of stability-indicating assays, including size and charge variants, fragmentation, particulate formation, protein concentration, and potency. No significant ABP 215 degradation was observed across the tested conditions. Although we acknowledge that higher order structural determination is important in the development of any pharmaceutical product [22], we did not use spectroscopy-based techniques to assess the impact of extended storage and infusion on the secondary or tertiary structure of ABP 215 in this study. However, the combination of chromatographic and biological techniques used provide a reliable indication of the structural integrity of the molecule. Furthermore, the higher order structure of ABP 215 compared with reference bevacizumab has previously been reported using Fourier-transform infrared spectroscopy and UV circular dichroism, while the thermal stability of the two products was previously compared using differential scanning calorimetry [11]. These results demonstrate that ABP 215 is physically and chemically stable in 0.9% saline diluent for IV administration for up to 35 days at 2°C–8°C, followed by 2 days storage at 30°C, and is compatible with commonly used IV bags and tubing assembly materials. Analysis of ABP 215 by SE-HPLC indicated that the levels of HMW species present in the low-dose samples (1.4 mg/mL) were lower than in the high-dose samples (16.5 mg/mL). This is due to a reduction of the reversible self-association of ABP 215, and thus a lower level of HMW species, in the diluted low-dose samples and so does not reflect a difference in stability of ABP 215 drug product when diluted at different concentrations.
The ABP 215 drug product lots utilized in this study were both commercial lots manufactured using two different commercial drug product lots. The drug product lots were approximately 18 months old when the study was initiated. A potential limitation of this study was that non-major degradation pathways were not included.
These data support the advance preparation of ABP 215 in IV bags at concentrations of 1.4 mg/mL–16.5 mg/mL and storage at 2°C–8°C for up to 35 days, followed by storage at room temperature (up to 30°C) for up to 2 days. This allows for ABP 215 IV bags to be prepared in a central pharmacy and stored refrigerated until needed, and then transported at room temperature to clinical oncology sites for administration to the patient. This flexibility could benefit pharmacists and nurses, allow for use of dose-banding, and potentially reduce drug wastage. It might also benefit patients by reducing waiting times and providing them with the possibility of receiving ABP 215 treatment in satellite clinics closer to their homes.
To the best of our knowledge, this is the first study to investigate the extended in-use stability of a bevacizumab biosimilar (ABP 215). The originator product, bevacizumab, has been shown to be stable after dilution when stored at 2°C–8°C for 30 days, followed by 48 hours at 2°C–30°C [4]. The physicochemical properties of another bevacizumab biosimilar were also shown to be similar to reference bevacizumab following dilution and storage at 2°C–8°C for 24 hours [23]. Extended stability studies have also been performed on biosimilars of rituximab, infliximab and trastuzumab [24-27]. Biosimilars to rituximab and infliximab demonstrated stability when diluted and stored at 2°C–8°C for 14 or 30 days, followed by 24 hours at room temperature, and when stored at 4°C and 25°C for 7 days, respectively [24, 27]. The trastuzumab biosimilars, CT-P6 and ABP 980, exhibited stability following dilution and storage at 2°C–8°C for 1 month, followed by 24 hours at room temperature, and storage at 2°C–8°C or 30°C for 5 weeks, followed by 48 hours at 30°C, respectively [25, 26].
Conclusion
Using a range of stability-indicating assays, this study showed that ABP 215 was physically and chemically stable when diluted to both low- and high-dose concentrations for IV administration, stored for up 35 days at 2°C–8°C, followed by 2 days at 30°C, and subsequent worst-case infusion duration. These in-use stability data build on the available stability data for the originator product, bevacizumab [4] and for other bevacizumab biosimilars [23], and support the feasibility of the preparation and distribution of ABP 215 from centralized hospital pharmacies.
For patients
Drugs administered intravenously, such as cancer treatments, are prepared in an infusion bag at the specific dose needed by the patient. The quality of the drug needs to be maintained if these prepared infusion bags are to be stored for a period of time prior to use. This study tested whether the stability of the cancer drug MVASITM (also called ABP 215, a drug that is essentially the same as Avastin ® [bevacizumab]) is affected following dilution and storage for a length of time and at a range of temperatures similar to those used during real-world treatment. The results of this study show that the quality and stability of both high and low doses of MVASITM were maintained after being stored in two different types of infusion bag in the refrigerator for around a month, followed by storage at room temperature for 2 days, and finally following simulated infusion. This means that specific doses of MVASITM can be prepared in advance in hospital pharmacies and stored in a refrigerator as needed before distribution to the clinic ready for administration to the patient. This advance preparation could save the hospital time and money and reduce patient waiting times.
Acknowledgements
Medical writing support funded by Amgen Europe (GmbH) was provided by Hayley Owen, PhD, and Dawn Batty, PhD, Bioscript Medical Ltd, Macclesfield, UK.
Funding sources
This study was funded by Amgen Inc.
Prior presentations
An abstract reporting these data was originally submitted to the 25th Congress of the European Association of Hospital Pharmacists, which was due to be held in March 2020, but was subsequently postponed due to the coronavirus pandemic. The associated poster will now be presented at the rescheduled meeting, which will be held on 24–26 March 2021 in Vienna, Austria.
Competing interests
All authors are employees and stockholders of Amgen Inc.
Provenance and peer review: Not commissioned; externally peer reviewed.
Authors
Jolita Seckute1, PhD Ingrid Castellanos2, PhD Steven Bane1, PhD
1Process Development, Amgen Inc, Cambridge, MA, USA 2Attribute Sciences, Amgen Inc, Cambridge, MA, USA
References 1. Thomas M, Thatcher N, Goldschmidt J, Ohe Y, McBride HJ, Hanes V. Totality of evidence in the development of ABP 215, an approved bevacizumab biosimilar. Immunotherapy. 2019;11(15):1337-51. 2. U.S. Food and Drug Administration. Avastin [homepage on the Internet]. [cited 2020 Sep 25]. Available from: https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=125085 3. European Medicines Agency. Avastin [homepage on the Internet]. [cited 2020 Sep 25]. Available from: https://www.ema.europa.eu/en/medicines/human/EPAR/avastin 4. European Medicines Agency. Annex I. Avastin – Summary of product characteristics [homepage on the Internet]. [cited 2020 Sep 25]. Available from: https://www.ema.europa.eu/en/documents/product-information/avastin-epar-product-information_en.pdf. 5. Genentech Inc. Avastin – full prescribing information [homepage on the Internet]. [cited 2020 Sep 25]. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/125085s331lbl.pdf 6. Casak SJ, Lemery SJ, Chung J, Fuchs C, Schrieber SJ, Chow ECY, et al. FDA’s approval of the first biosimilar to bevacizumab. Clin Cancer Res. 2018;24(18):4365-70. 7. U.S. Food and Drug Administration. MVASI [homepage on the Internet]. [cited 2020 Sep 25]. Available from:https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&applno=761028 8. European Medicines Agency. MVASI [homepage on the Internet]. [cited 2020 Sep 25]. Available from: https://www.ema.europa.eu/en/medicines/human/EPAR/mvasi 9. Amgen. MVASI – full prescribing information [homepage on the Internet]. [cited 2020 Sep 25]. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/761028s004lbl.pdf 10. European Medicines Agency. MVASI – summary of product characteristics [homepage on the Internet]. [cited 2020 Sep 25]. Available from: https://www.ema.europa.eu/en/documents/product-information/mvasi-epar-product-information_en.pdf 11. Seo N, Polozova A, Zhang M, Yates Z, Cao S, Li H, et al. Analytical and functional similarity of Amgen biosimilar ABP 215 to bevacizumab. MAbs. 2018;10(4):678-91. 12. Hanes V, Chow V, Pan Z, Markus R. A randomized, single-blind, single-dose study to assess the pharmacokinetic equivalence of the biosimilar ABP 215 and bevacizumab in healthy Japanese male subjects. Cancer Chemother Pharmacol. 2018;82(5):899-905. 13. Markus R, Chow V, Pan Z, Hanes V. A phase I, randomized, single-dose study evaluating the pharmacokinetic equivalence of biosimilar ABP 215 and bevacizumab in healthy adult men. Cancer Chemother Pharmacol. 2017;80(4):755-63. 14. Thatcher N, Goldschmidt JH, Thomas M, Schenker M, Pan Z, Paz-Ares Rodriguez L, et al. Efficacy and safety of the biosimilar ABP 215 compared with bevacizumab in patients with advanced nonsquamous non-small cell lung cancer (MAPLE): a randomized, double-blind, phase III study. Clin Cancer Res. 2019;25(7):2088-95. 15. Chatelut E, White-Koning ML, Mathijssen RH, Puisset F, Baker SD, Sparreboom A. Dose banding as an alternative to body surface area-based dosing of chemotherapeutic agents. Br J Cancer. 2012;107(7):1100-6. 16. Reinhardt H, Trittler R, Eggleton AG, Wohrl S, Epting T, Buck M, et al. Paving the way for dose banding of chemotherapy: an analytical approach. J Natl Compr Canc Netw. 2017;15(4):484-93. 17. Finch M, Masters N. Implications of parenteral chemotherapy dose standardisation in a tertiary oncology centre. J Oncol Pharm Pract. 2019;25(7):1687-91. 18. Fahey OG, Koth SM, Bergsbaken JJ, Jones HA, Trapskin PJ. Automated parenteral chemotherapy dose-banding to improve patient safety and decrease drug costs. J Oncol Pharm Pract. 2020;26(2):345-50. 19. NICE. Chemotherapy dose standardisation. 2019 [homepage on the Internet]. [cited 2020 Sep 25]. Available from: https://www.nice.org.uk/advice/ktt22/chapter/Evidence-context 20. NHS England. National dose banding table – bevacizumab 25mgmL [homepage on the Internet]. [cited 2020 Sep 25]. Available from: https://www.england.nhs.uk/publication/national-dose-banding-table-bevacizumab-25mgml/ 21. Machado S, Cainé G, Landeira N, Pereira M. Dose banding – optimising doses in cetuximab or bevacizumab regimens. EJHP. 2019;26(Suppl 1):A1-A311. 22. Astier A. Importance of the determination of the higher order structure in the in-use stability studies of biopharmaceuticals. Generics and Biosimilars Initiative Journal 2020;9(2):49-51. doi:10.5639/gabij.2020.0902.009 23. Arvinte T, Palais C, Poirier E, Cudd A, Rajendran S, Brokx S, et al. Part 2: Physicochemical characterization of bevacizumab in 2 mg/mL antibody solutions as used in human i.v. administration: comparison of originator with a biosimilar candidate. J Pharm Biomed Anal. 2019;176:112802. 24. Lamanna WC, Heller K, Schneider D, Guerrasio R, Hampl V, Fritsch C, et al. The in-use stability of the rituximab biosimilar Rixathon®/Riximyo® upon preparation for intravenous infusion. J Oncol Pharm Pract. 2019;25(2):269-78. 25. Crampton S, Polozova A, Asbury D, Lueras A, Breslin P, Hippenmeyer J, et al. Stability of the trastuzumab biosimilar ABP 980 compared to reference product after intravenous bag preparation, transport and storage at various temperatures, concentrations and stress conditions. Generics and Biosimilars Initiative Journal. 2020;9(1):5-13. doi:10.5639/gabij.2020.0901.002 26. Kim SJ, Lee JW, Kang HY, Kim SY, Shin YK, Kim KW, et al. In-use physicochemical and biological stability of the trastuzumab biosimilar CT-P6 upon preparation for intravenous infusion. BioDrugs. 2018;32(6):619-25. 27. Vieillard V, Astier A, Sauzay C, Paul M. One-month stability study of a biosimilar of infliximab (Remsima®) after dilution and storage at 4°C and 25°C. Ann Pharm Fr. 2017;75(1):17-29.
Author for correspondence: Jolita Seckute, PhD, Process Development Senior Scientist, Amgen Inc, 360 Binney St, Cambridge MA 02142, USA
Disclosure of Conflict of Interest Statement is available upon request.
Permission granted to reproduce for personal and non-commercial use only. All other reproduction, copy or reprinting of all or part of any ‘Content’ found on this website is strictly prohibited without the prior consent of the publisher. Contact the publisher to obtain permission before redistributing.
Author byline as per print journal:Arianna Bertolani, PhD; Claudio Jommi, MS
Study Objectives: Different policies have been implemented to enhance uptake of biosimilars. Regarding policies focussing on the demand-side, the literature has mainly concentrated on interchangeability and substitutability recommendations, issued by national or regional policymakers. Information on actions taken by healthcare organisations (HCOs) regarding prescribing behaviour is limited. Furthermore, there is no evidence on whether local authorities implemented a policy framework aimed to appropriately reallocate resources gained through patent expiration. This paper aims to fill these gaps, investigating policies on biosimilars implemented at the local level in the Italian National Health Service. Materials and Methods: Data were retrieved through a structured, validated questionnaire, administered online to all 199 public HCOs. Results: Seventy-six organizations in 16 of 21 Italian regions completed the survey, 89% of HCOs implemented information/educational initiatives on biosimilars. Prescription targets on biosimilars versus originators and off-patent versus in-patent molecules were introduced in 62% and 75% of HCOs, respectively. Prescribers reaching targets are mostly rewarded through monetary incentives. 75% of HCOs performed systematic impact evaluation of biosimilars. However, only 21% of HCOs detect patient under-treatment due to budget constraints and how availability of cheaper drugs could help. Furthermore, according to 25% of respondents, their HCO is involved in studies on biosimilars, but respondents did not provide any evidence of these studies. Discussion and conclusions: The study shows a high level of proactivity by Italian HCOs regarding actions on prescribing behaviour for off-patent biologicals. However, it seems that structured actions aimed at appropriately reallocating resources gained through patent expiration are still lacking.
Introduction
The European Medicines Agency (EMA) defines a biosimilar as a biological medicine highly similar to another biological medicine already approved in the EU (reference medicine) in terms of structure, biological activity and its efficacy, safety and immunogenicity profile. The first biosimilar was approved by EMA in 2006 [1]. Since then, 54 biosimilars have been approved in Europe, nine authorizations were withdrawn after approval, and two applications were refused (up to April 2020). The approved biosimilars include growth factors (epoetins, filgrastim, pegfilgrastim), hormones (follitropin-α, insulin glargine and lispro, somatropin, teriparatide), low molecular weight heparins (enoxaparin sodium), monoclonal antibodies (adalimumab, infliximab, rituximab, bevacizumab, trastuzumab) and fusion proteins (etanercept) [2].
Due to the natural variability and more complex manufacturing of biological medicines, a biosimilar is not considered to be a generic of a biological medicine. This has ignited a debate regarding the interchangeability of biosimilars, which is defined as ‘the possibility of exchanging one medicine for another that is expected to have the same clinical effect’. This can refer to replacing a reference medicine with a biosimilar (or vice versa) or replacing one biosimilar with another. Replacement can be done by: (i) switching, which is when the prescriber decides to exchange one medicine for another with the same therapeutic intent; (ii) automatic substitution, which is the practice of dispensing one medicine instead of another interchangeable medicine at the pharmacy level without consulting the prescriber [1].
Akin to generics, biosimilars have the opportunity to create competition, offer less expensive alternatives to existing medicines, and/or push alternative medicines to lower their prices due to biosimilar competition [3, 4]. This increases the availability of financial resources, which is important in an era of restricted healthcare budgets [5–7]. Savings from biosimilars can be used to: (i) fund new and costly medicines required for unmet needs, or that provide an added therapeutic value to existing therapies; (ii) fund other healthcare services/initiatives; (iii) generate savings; or (iv) increase the number of patients treated due to lower treatment costs. Several budget-impact studies have estimated savings from biosimilar introduction and/or the related number of additional patients that can potentially be treated with these liberated resources in different European countries [8–10]. Two studies assessed the savings achievable by using biosimilar filgrastim for the treatment of chemotherapy-induced febrile neutropenia and biosimilar follitropin-α for the treatment of anaemia, simulating their reinvestment to increase the number of patients treated with new targeted antineoplastic drugs [11, 12].
Diversified policies have been implemented in Europe, both at the national, regional and local level, to increase the use of biosimilars in clinical practice. These have exhibited differences, in terms of uptake of biosimilars and related savings, even when implemented in the same country [3]. Policies developed by national policymakers are related to the supply and demand of biosimilars. On the supply-side, these include pricing and reimbursement procedures [13], e.g. internal reference pricing (IRP), external reference pricing (ERP); and recommendations on tendering practices that might influence pricing strategies of the industry at regional and local levels. On the demand-side, these include interchangeability and substitutability [14] recommendations, possibly supported by post-marketing evidence on the switch from originators to biosimilars [15]. However, most of the demand-side policies are implemented by regional and local payers, including educational programmes/information campaigns, pharmaceutical prescription budgets, prescription quotas, monitoring of prescriptions patterns, financial incentives or penalties. These payers are also mostly responsible for procurement procedures [16].
Both supply- and demand-side measures are important to achieve savings from biosimilars and regulatory authorities should find a balance between the implementation of these different policies. Only introducing price reductions, without including demand-side measures, typically limits the use of biosimilars [17]. However, appreciable price reductions may play an important role in countries where access to biologicals is limited due to the high prices of originators and high co-payments, such as many of those in Central and Eastern Europe [18].
Policies on biosimilars have been investigated in the recent literature. We performed a literature search on MEDLINE (PubMed) and Web of Science with the purpose of identifying the most important peer reviewed, original research articles published, in English, on policies on biosimilars implemented at local level. The literature search was performed using the following key terms: ‘biosimilar medicines’, ‘demand- and supply-side measures’, ‘local policies’, ‘prescribing targets’, ‘tender’ and ‘educational programmes’. Articles were selected for further analysis based on title and abstract screening. The search was supplemented by a manual review of the reference lists of identified articles.
Some studies focused on nationwide policies, e.g. recommendations on interchangeability, automatic substitutability, tendering procedures [19, 20], while others, using literature review and/or interview/survey methods, investigated the adoption of both national, regional and local policies, generally comparing the regulatory landscape of different countries [3, 21-23]. Very few studies have empirically investigated the impact of these policies. The impact of incentive schemes to encourage biosimilar uptake was assessed by Rémuzat et al. across several European countries [22]. The study found a correlation between incentive policies and the uptake of biosimilars, but the presence of incentive schemes was surveyed at the national level, and heterogeneity of the local measures adopted was disregarded. Moorkens et al. appraised the effect of biosimilar policies and initiatives on market dynamics for infliximab and etanercept among regions in Sweden [24, 25]. Variations in the market share of biosimilars between the Swedish regions, especially regarding infliximab, were found to be largely explained by the discounted price difference between the biosimilar and the originator, thus depending more on supply-side than demand-side policies. Another study by Curto et al. investigated regional policies on tenders in Italy and found important differences in actual prices charged in different regions [26, 27].
In most cases, the reported evidence does not account for the heterogeneity of the policies implemented at the local level. Furthermore, no study has investigated whether healthcare organisations (HCOs): (i) have implemented systematic, prospective and/or retrospective impact evaluation of biosimilars; and (ii) planned in advance how to invest resources made available by treatment cost reduction. As outlined above, these resources can be used to increase patient access to these treatments, fund new and innovative medicines and other healthcare services, and/or simply accumulate savings.
This paper aims to address the information gaps identified. It will investigate local biosimilars policies and uncover whether they are driven by prospective and/or retrospective impact evaluations of biosimilars; and if there have been structured analyses of how to invest resources made available by treatment cost reduction.
The analysis was carried out in Italy. Here, the Italian National Health Service (INHS) represents an interesting case study due to its fragmentation. Variations across HCOs can be attributed to both regional and intra-regional differences.
Italian policies on biosimilars
Italy has a decentralized healthcare system and biosimilar policies have been developed by national, regional and local policymakers. The Italian Medicines Agency (Agenzia Italiana del Farmaco, AIFA) issued two position papers on biosimilars in 2013 and 2018, respectively [28, 29]. In both documents, AIFA notes that the comparability exercise performed by EMA is sufficient to define biosimilars as interchangeable with the related originators both for naïve and non-naïve patients and, as specified in the more recently released version, in terms of quality, safety and efficacy aspects, even in the case of extrapolation of therapeutic indications. However, AIFA advised that the final decision on interchangeability should be left to the prescriber. Regulation for tenders that involve off-patent biological medicines was enacted in 2016 (Law 232/2016). According to this regulation: (i) one lot cannot contain chemically different active principles, even if they are authorized for the same therapeutic indication; (ii) framework agreements must be used if more than three biological medicines based on the same active ingredient are present on the market; and (iii) clinicians should choose between one of the first three drugs identified according to the lowest price or the lowest bid criterion in the framework agreement.
In Italy, Regional Health Authorities (RHAs) are responsible for planning healthcare services, allocating financial resources to healthcare providers and promoting actions to influence the prescribing behaviour, including educational programmes and, moreover, pharmaceutical tendering. Local health authorities are responsible for implementing national and regional policies at a local level, but they are also able to introduce new actions or integrate existing ones [30].
For example, RHAs are free to set or recommend prescriptions targets to HCOs, with related incentives and/or sanctions for clinicians, and/or usage guidelines for biosimilars. Local health authorities can decide to implement these policies as they have been developed at the regional level or to integrate them with further directives. Additionally, local payers might also introduce these policies autonomously, if such recommendations are not made at the regional level. In general, these policies might be implemented to increase savings in those regions affected by mandated Recovery Plans, i.e. regions with important healthcare deficits who must adopt expenditure containment measures.
In 2018, prescriptions of biosimilars accounted for 19% and 25% of the total market for off-patent medicines with at least one available biosimilar, in terms of expenditure and consumption, respectively. The biosimilar market share (expressed as consumption incidence) ranges from 79.4% for epoetin, to 2% for adalimumab. There are also differences in biosimilar market share across regions [31].
Materials and methods
A literature search of local policies on biosimilars was carried out as described above. Data were collected on local policies using a survey distributed to HCOs. A web-based questionnaire, consisting of 40 closed and open-ended questions, was delivered to the general managers of all 199 Italian public HCOs, which includes local health authority and independent hospitals. The questionnaire was sent by email to the target respondents for completion between October 2019 and January 2020. Three reminder email messages were sent after sending the original questionnaire. The individual respondents were directly contacted in case of incomplete surveys.
The questionnaire related to all commercially available biosimilars and was divided into five sections. The first section focused on educational/information programmes on biosimilars, that are important both for physicians and patients to prevent the ‘nocebo’ effect [32]. Investigation included examination of their implementation by year, frequency, main topic(s) of the programme, i.e. biosimilar pipelines, comparative exercise and marketing authorization process, market access pathway for biosimilars, information on the results of tenders; and key target audiences, i.e. clinicians, hospital pharmacists, patients, administrative staff.
The second section aimed to collect information on the prospective and retrospective impact evaluations of biosimilars. The systematic implementation of these analyses by HCOs was investigated along with their subject, i.e. total savings, price reduction, prescribing shift from off-patent (with biosimilars) to patent-protected molecules for the same or similar indication; increase in the number of treated patients due to the lower treatment cost, time horizon and update rate.
The third section investigated whether HCOs estimate the proportion of the target population indicated for biological treatments who may not receive treatments due to budget constraints.
The fourth section explored the implementation of prescription targets and related incentive or sanction schemes, e.g. possibility to reallocate resources gained for new and expensive medicines or for other healthcare services, and withdrawal of the authorization to prescribe. More specifically, the study distinguishes between prescription targets for the same molecule (larger market share for biosimilars or the cheapest products) and those for different molecules sharing the same or similar indications (larger market share for the cheapest molecules in the same therapeutic class). We scrutinized incentive schemes, i.e. rewarding physicians who reach the prescription targets, and sanction schemes, i.e. sanctions for physicians who do not reach the prescription targets. Incentive schemes could be financial, e.g. bonus, or non-financial, e.g. earned autonomy, and intended to change the behaviour of prescribers (direct incentives, e.g. bonus) or patient’s choice of providers (indirect incentives, e.g. cost differentials for patients) [33]. The focus was on direct incentives including financial incentives (bonus), or non-financial incentives, e.g. including allowing prescribers to use free-up resources for innovative but expensive medicines to treat more patients; or to reallocate these resources for other healthcare services, e.g. diagnostics. Sanctions may range from monetary sanctions to a withdrawal of the authorization to prescribe.
The fifth section of the questionnaire aimed to collect evidence on the participation of HCOs in post-marketing studies on biosimilars. More specifically, it surveyed the study type, i.e. effectiveness and safety profile studies, patient compliance, impact evaluation of policies on prescribing behaviour, perceptual surveys targeting patients and healthcare professionals; the year of the study and the availability of grey and/or peer-reviewed references.
The structured questionnaire was validated by two potential respondents before it was administrated to the final target population. The questionnaire was written in Italian. All the collected data are related to 2019 (or last available year), except for educational/information programmes for which the adhesion rate since 2016 was investigated. Missing values were not countered for in the relevant questions.
The next section discusses the sample size. The representativeness of this sample is measured in terms of: (i) the number of respondents; and (ii) the dimension of the relevant HCOs, using HCO total reimbursement funding as an indicator of dimension. Since the 199 HCOs include both local health authorities and independent hospital trusts, other indicators, e.g. number of beds or the relevant population, were not feasible. The descriptive analysis presented in the next section were performed using Microsoft excel.
Results
The HCOs survey response rate was 38% nationwide (39% in terms of total HCO total reimbursement funding, as a proxy of the dimension of the HCO), and 47%, 33% and 27% (47%, 26%, 35% in terms of total reimbursement funding) in the Northern, Central and Southern regions, respectively. The majority of all regions (16 out of the 21 regions, accounting for 93% of the Italian population [34]) are represented with a region-specific response rate ranging from 11% to 100% of HCOs, see Figure 1a and 1b. The HCOs that did not complete the questionnaire are located in small regions (between 1% to 2% in terms of total HCO total reimbursement funding) in which there are few local health authorities (in some cases, only one). Most respondents (80%) completed more than 90% of the questionnaire, and only 5% answered less than 70% of questions.
Educational programmes on biosimilars have been carried out in almost all HCOs, with an increasing trend in recent years (from 20% of HCOs in 2016, to 89% in 2019). These programmes have mainly focused on the market access pathway for biosimilars in Italy (83% of the HCOs) and the relevant region (88%), followed by information on the results of tenders (60%), comparability exercises to obtain marketing approval and marketing authorization processes (26%), and biosimilar pipelines (19%). Clinicians and hospital pharmacists are the main targets of these programmes (97% and 77% of the initiatives, respectively). Patients were involved in educational/information programmes on biosimilars in only 22% of the HCOs. These figures are very similar across respondent regions.
We investigated whether HCOs systematically predict and/or ex post evaluate the impact of patent expiration of biological medicines and the availability of biosimilars. It seems that this activity is quite common. Prospective and retrospective impact evaluations are carried out by 75% of the HCOs, 18% of the HCOs systematically evaluate only ex post effects, and 7% do not conduct any analysis. The impact of patent expiration can be prospectively or retrospectively measured in terms of total savings, price reduction, prescribing shift from off-patent (and with biosimilars) to patent-protected molecules for the same or similar indication and increase of treated patients due to a price reduction. On average, HCOs are more interested in investigating total savings and prescribing shift from off-patent to patent-protected medicines. To a lesser extent, prospective analyses are carried out by regions subject to Recovery Plans, however these regions should be more engaged in these analyses as they are required to cover healthcare spending deficits. The same regions pay more attention, both prospectively and retrospectively, to the prescribing shift. It seems that these regions are more concerned with potential inappropriateness of this shift from off-patent to patent-protected molecules, see Table 1.
Only 21% of the HCOs assessed the untreated proportion of the target population for biological treatments. Coverage improvement due to lower costs derived from patent expiration, is estimated in half of these regions.
The objective of increasing the proportion of biosimilar prescriptions (or the cheapest products) is communicated to prescribers by 75% of HCOs. A lower proportion of HCOs (62%) provide physicians with prescription targets for off-patent medicines within the same therapeutic class, e.g. encouraging physicians to prescribe cheaper antitumour necrosis factor-alpha (anti-TNF-α). Among the HCOs providing prescription targets, 68% and 24% rely on incentives and sanctions, respectively. Regions affected by Recovery Plans have implemented these policies in similar proportions to the other regions, but they rely less than others on incentives and more on sanctions.
Rewards include monetary incentives or allowing prescribers to reallocate resources gained for new and expensive medicines, to either treat new patients or to enable physicians to use these resources for other healthcare services, e.g. diagnostics. Monetary incentives account for 56% of reward policies and prevail in the Northern regions; reallocation to new medicines is more frequent in the Central and Southern regions of Italy, see Figure 2A. Similar results are found for incentives and sanctions linked to broader prescription targets within therapeutic classes. In very few cases, savings are redirected to other healthcare services, see Figure 2B. Where sanctions are applied, they are mostly monetary; in a single case, authorization to prescribe was withdrawn.
Finally, 25% of the HCOs reported participation in post-marketing studies on biosimilars. These studies are focused on the safety profile (31% of total cases reported) and the impact of policies on prescribing behaviour (31%), followed by biosimilar effectiveness (16%). Perceptual surveys, targeting patients and healthcare professionals were less frequent (9% and 3%, respectively). Respondents did not provide any grey or peer-reviewed references resulting from these studies.
Supplementary Material (questionnaire and complete set of results) is available on request.
Discussion
Patent expiration and price-competition generated by biosimilar medicines give healthcare systems an opportunity to liberate and redirect resources. These resources can be invested in new medicines approved for unmet needs and severe diseases, or those that bring added therapeutic value to existing alternatives; or they can be used to improve access to medicines as the treatment cost reduces. HCOs may also utilize these resources for other healthcare services or simply as savings. Both demand- and supply-side measures implemented by the regulatory authorities are important to enhance the cost savings achieved by the introduction of biosimilars [21].
Most of the studies on biosimilar policies have focused either on supply-side measures, e.g. price regulation, or on recommendations issued by central authorities on interchangeability and/or substitutability issues. Little empirical evidence on the role played by local payers has been published thus far, in particular with reference to actions aimed at governing prescribing behaviour [28, 29]. Furthermore, the published evidence has not highlighted the heterogeneity of adopted solutions at the local level and the existence of a general framework for policy design and implementation. This paper is intended to fill this gap, using Italy as a case study as its decentralized health system provides interesting insight into the convergence and divergence of local policies.
The study has revealed that there has been huge investment in biosimilar policies by respondent HCOs. Educational programmes on biosimilars have been carried out in almost all HCOs. Some 93% of HCOs conduct retrospective and/or prospective assessment of the impact of patent expirations for biological drugs. Prescribers have been urged to increase prescriptions of biosimilars (or the cheapest product) within the same therapeutic class by 75% and 62% of HCOs, respectively. Incentive schemes mostly rely on monetary transfers and were applied by 68% of those HCOs that have introduced prescription targets, whereas penalties for prescribers who do not reach target levels are much less diffused.
However, it is clear that local initiatives still lack a general framework for policy design and implementation. For example, only 21% of the HCOs systematically estimate the proportion of the target population that is not receiving biological treatment. This information is useful to understand whether resources gained from biosimilar substitutions should be used to treat more patients and exploit the lower prices. Furthermore, in the face of widespread retrospective evaluation of the market impact of biosimilars, only 25% of HCOs declare having participated in post-marketing studies on biosimilars, and only 30% of these HCOs have carried out specific impact analyses of biosimilar policies, with no published evidence or references reported.
This current study has some limitations. Firstly, the sample accounts for 38% of public HCOs. It can be assumed that the HCOs which were more active in implementing policies were also those which were more likely to respond, generating a possible selection bias. Despite almost all regions (and all major regions) being represented, the proportion of respondents do vary across regions. Hence, we cannot state that the sample represents all HCOs in Italy. We also decided to include only public HCOs, since private accredited hospitals are very different across regions, ranging from small hospitals where biological treatments are not used at all, to highly specialized hospitals where biological treatments may represent a high proportion of the drug budget. Secondly, the study relied on the information provided by the respondents. Information on the HCO websites was limited, and cross-check analysis could not be performed. Thirdly, the impact of these policies on biosimilar penetration rates was not estimated. This has compromised the comparability of this research to the few other empirical studies which have investigated this topic through cross-country [22] and cross-regional [24, 25] comparisons. This research question was beyond the scope of this study and other policies may have affected this penetration rate, e.g. tenders, and actions on prescribing behaviour were not necessarily aimed at increasing biosimilar penetration rates, but on maximizing the impact of patent expiration.
Conclusions
Despite its limitations, this study provides broad and empirical information on the biosimilar policies implemented by HCOs that are part of the Italian National Health Service. These policies include educational and information programmes, prospective and retrospective analysis of the impact of patent expiration and biosimilars launch, prescription targets and incentive/sanction schemes, implementation of post-marketing studies on biosimilars, and estimates of patients not able to access biological medicines due to high treatment costs (the untreated) who could benefit from the availability of cheaper drugs. The findings have some important policy implications.
Firstly, variability in implemented policies was uncovered. However, variation across HCOs is not necessarily an issue as different policies are needed to solve different problems. For example, Southern regions have focused their prospective evaluation on prescription shifts from off-patent to patent protected molecules. This could be attributed to a higher perceived risk of an inappropriate prescription shift, whereas Northern regions were more focused on the impact on prices.
In addition, in Southern regions, where HCOs were more focused on prescription shifts in their prospective analysis, there has been a less pronounced introduction of prescription targets per therapeutic class. However, targets are provided exactly to avoid inappropriate prescription shifts. This highlights the importance of ensuring the internal consistency of policies.
Lastly, the study shows that in most HCOs a general framework to decide how to reallocate resources recovered as a result of biosimilar introduction is still lacking. This framework implies a systematic prospective and retrospective analysis of the impact of biosimilars and an evaluation of possible areas of under-treatment with biologicals. For example, a more diffused awareness of the extent of untreated patients is important to understand whether such regained resources should be prioritized for untreated patients or earmarked for other purposes, e.g. coverage of new molecules launched on the market.
Acknowledgements
The authors would like to thank Paolo Bordon (General Manager of Azienda Provinciale per i Servizi Sanitari – Trento) and Angelo Tanese (General Manager of Azienda Sanitaria Locale Roma 1) for having validated the questionnaire, and all participants in the survey. The authors thank Helen Banks (CERGAS, SDA Bocconi) and Lisa Pirrie (ApotheCom) for revision of the English text.
Funding sources
The present study was funded by Sandoz SpA through an unrestricted grant to CERGAS, SDA Bocconi School of Management. No interferences occurred in carrying out the research project and in writing the manuscript for which the authors are solely responsible.
Priori presentations: These results have not been presented before.
Competing interests: Arianna Bertolani and Claudio Jommi received an unrestricted grant from Sandoz, but no interferences occurred in carrying out the research project and in writing the manuscript for which the authors have the sole responsibility.
Provenance and peer review: Not commissioned; externally peer reviewed.
Authors
Arianna Bertolani, PhD, Junior Lecturer – Government, Health and Non-Profit Division Claudio Jommi, MS
Centre for Research on Health and Social Care Management (CERGAS), SDA Bocconi School of Management, Bocconi University, 10 Via Sarfatti, IT-20136 Milan, Italy
References 1. European Medicines Agency and the European Commission. Biosimilars in the EU: information guide for healthcare professionals. 2019 [homepage on the Internet]. [cited 2020 Sep 25]. Available from:https://www.ema.europa.eu/en/documents/leaflet/biosimilars-eu-information-guide-ealthcare-professionals_en.pdf 2. European Medicines Agency. European public assessment reports (EPARs) for human medicines [homepage on the Internet]. [cited 2020 Sep 25]. Available from: https://www.ema.europa.eu/en/medicines/download-medicine-data 3. Moorkens E, Vulto AG, Huys I, Dylst P, Godman B, Keuerleber S, et al. Policies for biosimilar uptake in Europe: an overview. PLoS One. 2017;12(12):e0190147. 4. Troein P, Newton M, Patel J, Scott K. The impact of biosimilar competition in Europe. IQVIA Report 2019 [homepage on the Internet]. [cited 2020 Sep 25]. Available from: https://ec.europa.eu/docsroom/documents/38461 5. Farfan-Portet MI, Gerkens S, Lepage-Nefkens I, Vinck I, Hulstaert F. Are biosimilars the next tool to guarantee cost-containment for pharmaceutical expenditures? Eur J Health Econ. 2014;15(3):223-8. 6. Dutta B, Huys I, Vulto AG, Simoens S. Identifying key benefits in European off-patent biologics and biosimilar markets: it is not only about price! BioDrugs. 2020;34:159-70. 7. Godman B, Allocati E, Moorkens E. Ever-changing landscape of biosimilars in Canada; findings and implications from a global perspective. Generics and Biosimilars Initiative Journal (GaBI Journal). 2019;8(3):93-7. doi:10.5639/gabij.2019.0803.012. 8. Gulácsi L, Brodszky V, Baji P, Rencz F, Péntek M. The rituximab biosimilar CT-P10 in rheumatology and cancer: a budget impact analysis in 28 European countries. Adv Ther. 2017;34(5):1128-44. 9. Jha A, Upton A, Dunlop WCN, Akehurst R. The budget impact of biosimilar infliximab (Remsima®) for the treatment of autoimmune diseases in five European countries. Adv Ther. 2015;32(8):742-56. 10. Rognoni C, Bertolani A, Jommi C. Budget impact analysis of rituximab biosimilar in Italy from the hospital and payer perspectives. Global Reg Health Technol Assess. 2018. doi:10.1177/2284240318784289. 11. Sun D, Andayani TM, Altyar A, MacDonald K, Abraham I. Potential cost savings from chemotherapy-induced febrile neutropenia with biosimilar filgrastim and expanded access to targeted antineoplastic treatment across the European Union G5 countries: a simulation study. Clin Ther. 2015;37(4):842-57. 12. Abraham I, Han L, Sun D, MacDonald K, Aapro M. Cost savings from anemia management with biosimilar epoetin alfa and increased access to targeted antineoplastic treatment: a simulation for the EU G5 countries. Future Oncol. 2014;10(9):1599-609. 13. Vogler S, Zimmermann N, Haasis MA. PPRI Report 2018. Pharmaceutical pricing and reimbursement policies in 47 PPRI network member countries. WHO Collaborating Centre for Pricing and Reimbursement Policies, Gesundheit Österreich GmbH (GÖG/Austrian National Public Health Institute). 2019 [homepage on the Internet]. [cited 2020 Sep 25]. Available from: https://ppri.goeg.at/sites/ppri.goeg.at/files/inline-files/PPRI%20Report2018_final.pdf 14. Vogler S, Schneider P. Do pricing and usage-enhancing policies differ between biosimilars and generics? Findings from an international survey. Generics and Biosimilars Initiative Journal (GaBI Journal). 2017;6: 79–88. doi:10.5639/gabij. 2017.0602.015. 15. Jørgensen KK, Olsen IC, Goll GL, Lorentzen M, Bolstad N, Haavardsholm EA, et al. Switching from originator infliximab to biosimilar CT-P13 compared with maintained treatment with originator infliximab (NOR-SWITCH): a 52-week, randomised, double-blind, non-inferiority trial. Erratum. Lancet. 2017;389(10086):2304-16. 16. WHO Collaborating Centre for Pharmaceutical Pricing and Reimbursement Policies. Glossary [homepage on the Internet]. [cited 2020 Sep 25]. Available from: https://ppri.goeg.at/ppri-glossary 17. Kim Y, Kwon HY, Godman B, Moorkens E, Simoens S, Bae S. Uptake of biosimilar infliximab in the UK, France, Japan and Korea. Budget savings or market expansion across countries? Front Pharmacol. 2020;11:970. 18. Baumgart DC, Misery L, Naeyaert S, Taylor PC. Biological therapies in immune-mediated inflammatory diseases: can biosimilars reduce access inequities? Front Pharmacol. 2019;10:279. 19. O’Callaghan J, Barry SP, Bermingham M, Morris JM, Griffin BT. Regulation of biosimilar medicines and current perspectives on interchangeability and policy. Eur J Clin Pharmacol. 2019;75(1):1-11. 20. Trifirò G, Marcianò I, Ingrasciotta Y. Interchangeability of biosimilar and biological reference product: updated regulatory positions and pre- and post-marketing evidence. Expert Opin Biol Ther. 2018;18(3):309-15. 21. Renwick MJ, Smolina K, Gladstone EJ, Weymann D, Morgan SG. Postmarket policy considerations for biosimilar oncology drugs. Lancet Oncol. 2016;17(1):e31-8. 22. Rémuzat C, Kapuśniak A, Caban A, Ionescu D, Radière G, Mendoza C, et al. Supply-side and demand-side policies for biosimilars: an overview in 10 European member states. J Mark Access Health Policy. 2017;5(1):1307315. 23. Acha V, Allin P, Bergunde S, Bisordi F, Roediger A. What pricing and reimbursement policies to use for off-patent biologicals in Europe? – Results from the second EBE 2014 biological medicines policy survey. Generics and Biosimilars Initiative Journal (GaBI Journal). 2015;4(1):17-24. doi:10.5639/gabij. 2015.0401.006. 24. Moorkens E, Simoens S, Troein P, Declerck P, Vulto AG, Huys I. Different policy measures and practices between Swedish counties influence market dynamics: Part 1-biosimilar and originator infliximab in the hospital setting. BioDrugs. 2019;33(3):285-97. 25. Moorkens E, Simoens S, Troein P, Declerck P, Vulto AG, Huys I. Different policy measures and practices between Swedish counties influence market dynamics: Part 2-biosimilar and originator etanercept in the outpatient setting. BioDrugs. 2019;33(3):299-306. 26. Curto A, Van der Vooren K, Garattini L, Lo Muto R, Duranti S. Regional tenders on biosimilars in Italy: potentially competitive? Generics and Biosimilars Initiative Journal (GaBI Journal). 2013;2(3):123-9. doi:10.5639/gabij.2013.0203.036. 27. Curto S, Ghislandi S, van de Vooren K, Duranti S, Garattini L. Regional tenders on biosimilars in Italy: an empirical analysis of awarded prices. Health Policy. 2014;116(2-3):182-7. 28. Agenzia Italiana del Farmaco (AIFA) – Position Paper. I farmaci biosimilari. 2013 [homepage on the Internet]. [cited 2020 Sep 25]. Available from: https://www.aifa.gov.it/documents/20142/0/AIFA_POSITION_PAPER_FARMACI_BIOSIMILARI.pdf/22e2c111-dbbd-5b96-fd9c-e29c057d8204 29. Agenzia Italiana del Farmaco (AIFA) – Secondo Position Paper AIFA sui farmaci biosimilari. 2018 [homepage on the Internet]. [cited 2020 Sep 25]. Available from: https://www.aifa.gov.it/sites/default/files/pp_biosimilari_27.03.2018.pdf 30. Jommi C, Costa E, Michelon A, Pisacane M, Scroccaro G. Multi-tier drugs assessment in a decentralised health care system. The Italian case-study. Health Policy. 2013;112(3):241-7. doi:10.1016/j.healthpol.2013.06.004 31. Agenzia Italiana del Farmaco (AIFA) – Osservatorio Nazionale sull’impiego dei Medicinali. L’uso dei farmaci in Italia. Rapporto Nazionale Anno 2018 [homepage on the Internet]. [cited 2020 Sep 25]. Available from: https://www.aifa.gov.it/documents/20142/0/Rapporto_OsMed_2018.pdf/c9eb79f9-b791-2759-4a9e-e56e1348a976 32. Pouillon L, Socha M, Demore B, Thilly N, Abitbol V, Danese S, et al. The nocebo effect: a clinical challenge in the era of biosimilars. Expert Rev Clin Immunol. 2018;14(9):739-49. 33. Custers T, Hurley J, Klazinga NS, Brown AD. Selecting effective incentive structures in health care: a decision framework to support health care purchasers in finding the right incentives to drive performance. BMC Health Serv Res. 2008;8:66. 34. I.STAT Database – Popolazione residente al 1° gennaio 2019 [homepage on the Internet]. [cited 2020 Sep 25]. Available from: http://dati.istat.it/Index.aspx?DataSetCode=DCIS_POPRES1#
Author for correspondence: Arianna Bertolani, PhD, Centre for Research on Health and Social Care Management (CERGAS), SDA Bocconi School of Management, Bocconi University, 10 Via Sarfatti, IT-20136 Milan, Italy
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Author byline as per print journal:Rieke Alten1, MD, PhD; Herbert Kellner2, MD; Malcolm Boyce3, MD; Takuma Yonemura4, MD; Takahiro Ito5, MSc; Mark C Genovese6, MD
Introduction/Study objectives: FKB327 is a biosimilar of the adalimumab reference product. Studies in healthy subjects and patients with rheumatoid arthritis demonstrated biosimilarity between FKB327 and the reference product in safety profile, efficacy and immunogenicity. FKB327 formulation excipients differ from the citrate-containing formulation of the reference product, and injection-site pain differences have been reported. The current analysis examines pooled data to assess the amount of injection-site pain resulting from injecting FKB327 using a pre-filled syringe, autoinjector, or vial/syringe versus the reference product. Methods: Data from four studies were pooled to compare injection-site pain upon subcutaneous administration of FKB327 versus the reference product. Pooled data were analysed to compare FKB327 with the reference product and to compare the autoinjector, pre-filled syringe and vial/syringe. Results: Data were analysed from 2007 assessments in 1,001 subjects. A linear mixed model of the injection-site pain visual analogue scale score across all studies showed a 12.6-point lower pain score for FKB327 versus the reference product (95% confidence interval, –14.3 to –10.8; p < 0.001). The autoinjector pain score was 4.4 points lower than the vial/syringe (95% confidence interval, –5.9 to –2.8; p < 0.001) and 1.7 points lower than the pre-filled syringe (95% confidence interval, –3.3 to –0.1; p = 0.035). No statistically significant differences were identified for gender, age, body weight, needle gauge, or injection site. Conclusion: FKB327 showed less injection-site pain compared with the reference product. No statistically significant differences were seen in injection-site reactions or related adverse events between FKB327 and the reference product or among FKB327 injection methods.
Submitted: 1 July 2020; Revised: 31 July 2020; Accepted: 31 July 2020; Published online first: 14 August 2020
Introduction/Study objectives
Adalimumab, a recombinant human monoclonal antibody against tumour necrosis factor-alpha, is indicated for the treatment of patients with rheumatoid arthritis; juvenile idiopathic arthritis; psoriatic arthritis; ankylosing spondylitis; hidradenitis suppurativa; plaque psoriasis; adult and paediatric Crohn’s disease; ulcerative colitis in adults; and non-infectious intermediate, posterior and panuveitis in adult patients [1, 2]. Injection-site reactions (ISRs) are commonly reported with biological therapies [3, 4]. Local ISRs are estimated to affect 12% to 37% of patients treated with adalimumab [5, 6]. Local ISRs include erythema, pruritus, pain, inflammation, rash, induration, itching and oedema [5], potentially causing patients stress, nervousness, reduced quality of life, and a negative impact on willingness to self-administer and adhere to medication [7]. ISRs typically occur during the first month of treatment, last for 3 to 5 days, and commonly resolve without additional therapy [5]. Most ISRs caused by adalimumab are mild to moderate and generally do not require drug discontinuation; but may lead to patient discomfort [2]. Risk factors for having hypersensitivity reactions depend on both the drug and the individual patient characteristics, i.e. disease for which the treatment is indicated, the patient’s immune status, and the concomitant treatments received [4, 8].
Among ISRs, injection-site pain (ISP) is an important element that has been reported with some biologicals due to several factors, including formulation, needle size, anatomic region of injection, and buffer [9]. Patient injection experience may be a significant factor in the selection of biological treatment and in discontinuing therapy to avoid pain and discomfort [10]. Among patients with rheumatoid arthritis, ISP can have an impact on treatment adherence, which is often suboptimal in routine clinical practice [11, 12].
The stability of the formulation of biologicals is improved by using additives such as buffers, amino acids and sugars. An association between ISP and the use of citrate as a buffer has been previously described [9]. Excipients are designated by the regulatory authorities to be inactive and not considered the primary, biologically active ingredient [13]. Excipients in monoclonal antibody therapies are intended to stabilize the active protein from manufacturing until its use by the patient [13]. It has been hypothesized that ISRs associated with products containing excipients are a result of the complement activation-derived inflammatory mediators; degradation of the excipient may be the causative factor [13].
Subsequently, it has been reported that the citrate-containing formulation (CCF) of the adalimumab reference product (RP), which was initially approved in the European Union, the US, and other countries, may be associated with ISP. The formulation excipients of the biosimilar product, FKB327, differ from those of the CCF-RP in that it does not contain citrate, and differing ISP with subcutaneous injection has been reported. FKB327 and the RP are formulated such that the pH of both products is approximately 5.2 [2, 14]. The primary objective of this analysis was to comprehensively characterize ISP and ISRs among patients with moderate-to-severe rheumatoid arthritis and healthy subjects treated with FKB327 compared with CCF-RP. The current analysis also examines pooled data from these studies comparing the amount of ISP resulting from injecting FKB327 using a pre-filled syringe (PFS), an autoinjector (AI), or a vial with regular syringe (RS) versus the CCF-RP.
Methods
Study design Data were derived from four randomized studies (FKB327-001, -002, -003, and -004) evaluating the efficacy, safety profile and pharmacokinetics (PK) of FKB327 in patients with rheumatoid arthritis and healthy subjects. The studies were conducted from April 2013 to January 2018. The designs of these studies have been previously published [15, 16] and the designs are available at clinicaltrials.gov (FKB327-002 [NCT02260791; EudraCT No.: 2014-000109-11] and -003 [NCT02405780; EudraCT No.: 20140000110-61] studies [dx.doi.org/10.17504/protocols.io.3r2gm8e]).
The studies were conducted in accordance with the Declaration of Helsinki and International Conference on Harmonization Guidelines for Good Clinical Practice. Study protocols were reviewed and approved by an independent ethics committee or institutional review board for each study centre. Written informed consent was obtained from all subjects and patients before study entry.
Studies 001 and 004 Study 001 was a randomized, double-blind, parallel-group phase I study comparing the safety profile and PK in healthy adult subjects after a single-dose of the study drug. Subjects were randomized to receive 40 mg of FKB327, the EU CCF-RP, or the US CCF-RP in a 1:1:1 ratio. The study drug was administered subcutaneously in the abdomen using identical syringes with 25-G 5/8 needles that had been pre-filled by pharmacy staff and labelled such that it was not possible to distinguish between FKB327 and either of the CCF-RPs.
FKB327-004 was a randomized, active-controlled, single-blind, parallel-group phase I clinical pharmacology study evaluating the safety profile and PK in Japanese healthy male subjects after a single-dose of the study drug. Subjects were randomized to receive 40 mg of either FKB327 or the CCF-RP in a 1:1 ratio. FKB327 PFS with a 29-G needle and CCF-RP with 27-G needle were administered subcutaneously in the abdomen. In both studies, PK was assessed by evaluation of serum concentrations of adalimumab. The safety profile was assessed by evaluation of safety laboratory tests, physical examination, vital signs, and electrocardiograms. In both studies, ISP and ISRs were assessed within 30 minutes of subcutaneous dosing and were monitored for 24 hours and 8 days or 4 days after single-dosing, respectively.
Studies 002 and 003 Study 002 was a multicentre, randomized, double-blind, parallel-arm, active-comparator phase III equivalence study to evaluate efficacy and safety profile similarity in patients with active rheumatoid arthritis. Patients were randomized in a 1:1 ratio to receive a 40-mg injection subcutaneously in the abdomen or thigh of either FKB327 (using a vial with RS and 30-G needle) or the CCF-RP (using a PFS and 27-G needle) every other week for 24 weeks.
This was followed by Study 003, a phase III open-label extension study, which consisted of two parts (Period I and Period II). In Period I, patients were rerandomized to receive either FKB327 (administered via PFS with 29-G needle) or CCF-RP (administered via PFS with 27-G needle) for 30 weeks, so that two-thirds of the patients continued the same treatment they had received in the preceding study and one-third received the alternate treatment. In Period II, patients were treated with FKB327 (single arm) for an additional 46 weeks. All patients outside the US were introduced to the FKB327 AI (using a 29-G needle) during Period II of this study.
Assessment of injection-site pain Pain at the injection site was assessed using a 100-mm visual analogue scale (VAS) score. In all four studies, subjects were asked to determine the extent of their pain by placing a small vertical mark on a horizontal line, with the left endpoint signifying ‘no pain’ and the right endpoint signifying ‘intolerable pain’. Subjects were able to see their previous responses to reduce variability. In the single-dose studies (Studies 001 and 004), assessments of ISP were performed immediately after dosing and at 0.5, 1, 12, and 24 hours post-dose. In the multiple-dose studies (Studies 002 and 003), assessments of ISP were performed within 30 minutes of administration of the first dose.
Assessment of injection-site reactions For all the studies, study staff applied light pressure at the injection site and recorded any tenderness, erythema and induration. The size of ISRs was measured along the longest axis.
Local reactions were assessed within 30 minutes of dosing according to the US Food and Drug Administration ‘Guidance for industry on skin irritation and sensitization testing of generic transdermal drug products’ as follows [17]:
In the single-dose studies (001 and 004), assessment of ISRs was performed immediately after dosing and at 12, 24, 48, 72 and 96 hours after injection; in addition, assessment of ISRs was performed at 192 hours in Study 001. In the multiple-dose studies (002 and 003), assessments were performed within 30 minutes of administration of the first dose.
Statistical analysis The analysis set included all the healthy subjects in the single-dose studies (assessment immediately after dosing) and all the patients in the multiple-dose studies (assessment within 30 minutes of dosing) who received the study drug and had ≥ 1 assessments of ISP and/or ISRs. Data from the four studies were pooled to compare FKB327 with the CCF-RP, the FKB327 methods of administration, i.e. PFS, AI, or vial with RS; and injection sites, i.e. abdomen or thigh. The comparison of the ISP VAS scores of FKB327 versus the CCF-RP was performed by using the linear mixed model with 8 fixed effects, consisting of subject population (healthy subject or patient with rheumatoid arthritis), age (< 50 years or ≥ 50 years), gender, race, ethnicity, body weight (< 70 kg or ≥ 70 kg), device (PFS, AI, or vial with RS), and treatment (FKB327 or CCF-RP), as well as two random effects: country and subject.
This analysis also evaluated the impact on ISP of differences in needle gauge (25 G, 27 G, 29 G, and 30 G) used in the various injections. The comparisons between FKB327 presentations and injection sites were performed using the same model. The thresholds of age and body weight were determined based on the median of actual data.
The results of the linear mixed model for the ISP VAS scores were reported with least squares means, 95% confidence intervals (CIs), and p values, where appropriate. The significance level of 5%, i.e. p < 0.05, indicated statistical significance. For Studies 002 and 003 in patients with rheumatoid arthritis, adverse events (AEs) related to ISRs were analysed by exposure-adjusted incident rate (per 100 patient-years) due to different treatment exposures between FKB327 and the CCF-RP, or among FKB327 methods of administration across the studies. All the analyses were performed by using SAS® version 9.1 (Cary, NC, US) or higher.
Results
Patient demographics Data analysed included a total of 2,007 assessments in 1,001 subjects and patients. The demographic and background data from the randomized subjects and patients with ISP data are shown by study in Table 1.
Injection-site pain Injection-site pain in individual studies In Study 001, immediately after dosing, subjects who received the EU- and US-sourced CCF-RP reported more ISP than subjects who received FKB327. Mean VAS scores were 5.5, 12.9, and 18.4 for the FKB327, EU CCF-RP, and US CCF-RP treatment groups, respectively. At all other time points, the VAS pain scores were similar across the treatment groups.
In Study 004, immediately after dosing, the VAS pain score was also lower in the FKB327 treatment group than in the CCF-RP treatment group. Mean VAS pain scores were 5.2 and 29.8 in the FKB327 and CCF-RP treatment groups, respectively. Thereafter, no substantial differences were observed in the VAS pain scores between the treatment groups.
In Study 002, at Day 1, patients in the FKB327 treatment group reported less pain than patients in the CCF-RP treatment group. Mean VAS scores were 9.3 and 20.2 in the FKB327 and CCF-RP treatment groups, respectively.
In Study 003, at Week 0, patients in the FKB327 treatment group reported less pain than patients in the CCF-RP treatment group. At Week 0 of Study 003, the mean VAS ISP score was slightly higher among patients who received the CCF-RP compared with patients who received FKB327 (12.9 vs 6.2). The mean VAS ISP score was slightly lower in patients who switched from the CCF-RP to FKB327 compared with those who received continuous treatment with the CCF-RP in Studies 002 and 003 (4.9 vs 11.1; see Table 2). Inversely, the mean VAS ISP score was slightly higher in patients who switched from FKB327 to the CCF-RP compared with those who received continuous FKB327 treatment (16.3 vs 6.8). At Week 30 of Study 003, the total mean VAS ISP score was 5.2, without any difference among treatment groups, because all patients were dosed with FKB327 via AI or PFS.
Of the 507 patients who switched to the AI device in Period II of Study 003, 423 patients had an ISP VAS score recorded at the time of switch. The mean VAS score did not change in patients who switched from the PFS device to AI device (F-F-F, 6.7-5.2; RP-F-F, 4.4-5.7), although it decreased in patients who switched from the CCF-RP to FKB327-AI (F-RP-F, 15.4-4.1; RP-RP-F, 7.4-4.5; see Table 3).
Pooled analysis of injection-site pain visual analogue scale score Because we observed numerical differences in ISP VAS score between patients treated with FKB327 and CCF-RP, we pooled the data from all four studies to increase the number of subjects and assess for statistical significance. A linear mixed model of the ISP VAS score for FKB327 versus the CCF-RP across all four studies showed a 12.6-point improvement (95% CI, –14.3 to –10.8; p < 0.001; see Table 4). The AI showed a 4.4-point lower VAS pain score compared with the RS (95% CI, –5.9 to –2.8; p < 0.001). The AI showed a 1.7-point lower VAS pain score compared with the PFS (95% CI, –3.3 to –0.1; p = 0.035). No statistically significant differences in ISP were identified for gender, age, body weight, population (healthy subject or patient), and injection site (thigh or abdomen). Although the difference in ISP VAS score was significant among races, the majority of subjects and patients were white.
A forest plot of the mean treatment difference of VAS scores showed favourability toward FKB327 over the CCF-RP in most subpopulations except for some countries and races, due to wide variability of 95% CI in a small number of subjects in the subpopulation, see figure 1.
Because of the differences in needle gauge used among the studies, we included needle gauge differences (25 G to 30 G) in the analysis. No statistically significant impact of needle gauge on pain VAS was observed (p = 0.786). Significantly lower pain VAS scores among those treated with FKB327 persisted even when needle gauge was included in the analytical model (–13.1; p < 0.001).
Injection-site reactions Single-dose studies In Study 001, the majority of subjects (94.4%) did not experience irritation at the injection site. Of the 10 subjects who experienced minimal erythema immediately post-dose, more subjects in the EU CCF-RP and US CCF-RP treatment groups (5 subjects [8.3%] and 4 subjects [6.7%]) experienced irritation than in the FKB327 treatment group (1 subject [1.7%]). Subjects receiving EU CCF-RP and US CCF-RP experienced more irritation and ISP immediately post-dose than those receiving FKB327. No subjects, including those experiencing minimal erythema immediately post-dose, had any evidence of irritation at subsequent time points (from 12 hours post-dose). In Study 004, the majority of subjects did not show any evidence of local site reactions. Local site reactions were reported slightly more frequently in the CCF-RP treatment group (9 subjects [13.8%]) than in the FKB327 treatment group (3 subjects [4.6%]) throughout the assessment period. In Study FKB327-004, ISR was reported in 12 (9.2%) subjects.
Multiple-dose studies The number of patients with ISRs and the nature of the reactions are presented in Table 5. A small number of patients with ‘minimal erythema, barely visible reaction’ was reported in the multiple-dose studies (3.1% at Week 0 of Study 002, 4.7% at Week 0 of Period I, and 2.7% at Week 30 of Period II of Study 003). Reports of ‘definitive erythema, readily visible reaction’ were low (0.8% at Week 0 of Study 002, 0.3% at Week 0 of Period I, and 0.7% at Week 30 of Period II of Study 003). No events were judged as ‘definite oedema’, ‘erythema, oedema and papules’, ‘vesicular eruption’, or ‘strong reaction spreading beyond test site’, nor were there any severe ISRs in the FKB327 or CCF-RP treatment groups. Overall, the number of patients with an ISR was very low. No important differences were observed in ISRs between the FKB327 and CCF-RP treatment groups or as a result of switching treatments.
Adverse events related to injection-site reactions Single-dose studies In Study 001, injection-site haematoma was one of the most common treatment-emergent AEs. Injection-site haematoma was reported for more subjects in the FKB327 treatment group (n = 4; 6.7%) than in the EU CCF-RP (n = 1; 1.7%) and US CCF-RP (n = 2; 3.3%) treatment groups. In Study 004, ISRs were reported in 3 (4.6%) subjects who received FKB327 and 9 (13.8%) subjects who received the CCF-RP.
Discussion
Advancements in the development of biologicals have provided improvements in local bioavailability and tolerability, as well as in maintaining drug stability against degradation or aggregation [18]. An association between ISP and the use of citrate as a buffer has been previously reported [9]. FKB327 was developed without citrate, which differs from the CCF-RP. In these studies, the adalimumab biosimilar FKB327 was associated with clinically significantly less ISP (12.6-point VAS score improvement) immediately after the first study drug dose than the CCF-RP. It has been reported that the minimum clinically significant difference in VAS pain score on a 100-mm scale is 9 mm to 10 mm, regardless of gender, age, or cause of pain [19, 20]. Therefore, the 12.6-point improvement in VAS pain score in subjects receiving FKB327 is a clinically meaningful change compared with those receiving the CCF-RP. In addition, advancements in the methods of delivery of adalimumab may also result in lower ISP than the standard vial with RS. In these studies, FKB327 delivered via AI showed a 4.4-point lower VAS pain score compared with the vial with RS and a 1.7-point lower VAS pain score compared with the PFS, although the small difference is not considered clinically meaningful [19, 20], while achieving similar PK and safety profiles. This suggests that the AI may be the preferred method of delivery for FKB327 when considering ISP.
In survey-based studies directed toward healthcare providers (HCPs) or consumers, 69% of all HCPs reported a preference for the use of an AI compared with a traditional syringe and needle [21]. HCPs identified benefits for administering injections using an AI, including ease of use, more consistent dosing, faster administration, and fewer needle-stick injuries. In addition, 90% of HCPs thought patients would be more adherent to therapy using an AI, which was supported by 86% of women who reported they would be more likely to adhere to therapy using an AI. A phase II study designed to compare the usability of an etanercept biosimilar via PFS and AI demonstrated that 81.1% of patients preferred the AI, 7.5% preferred the PFS, and 11.3% had no preference [22]. The AI was preferred in terms of all categories investigated, including convenience, ease of use, safety profile, time to administer injection, and decreased pain.
Additional benefits of using an AI include helping patients to overcome needle anxiety [23], allowing for use in patients with functional deficits [24], and improving treatment adherence and persistence [25]. AIs represent an alternative option to oral administration and the requirement for the use of vials and syringes. Benefits of AIs include a design wherein the needle is not visible, ease of use and a low level of associated pain. Together, these benefits of using an AI are thought to promote adherence and persistence of treatment.
A difference in administration between FKB327 and the CCF-RP was the needle gauge used. The FKB327 PFS and AI were manufactured with a 29-G needle, whereas the CCF-RP PFS contained a 27-G needle. Of importance, in the current study, the clinically meaningful differences in pain VAS scores between FKB327 and the CCF-RP persisted when we included needle gauge in the analytical model, demonstrating that needle gauge played no role in the differences in ISP observed between FKB327 and the CCF-RP.
A survey-based study investigating needle performance and patient preference for administration of glatiramer acetate for multiple sclerosis treatment revealed that significantly fewer patients reported problems after 30 days of use (including fewer injection-site experiences) and more patients preferred the 29-G needle overall compared with a 27-G needle [26]. In a study investigating 30-G needles versus 32-G needles for injection of botulinum toxin type A, the average injection pain scores were nominally but not significantly different in the arm or the face [27]. Furthermore, there were no clinically significant differences in pain associated with needle type following arm injections, with no significant differences in the character of clinically important pain. A Cochrane review demonstrated low-quality evidence that a wide needle (23 G) may slightly reduce pain associated with a vaccination procedure in 1,135 healthy infants compared with a narrow needle (25 G); however, these differences were thought to be too small to be of practical importance [28]. In a randomized crossover comparison of ISP with 40 mg/0.4 mL (29-G needle) or 40 mg/0.8 mL (27-G needle), significantly lower injection-related pain immediately after injection was reported for the 40 mg/0.4 mL formulation [29]. However, it is unclear whether the pain reduction was most attributable to differences in composition, volume and/or needle size.
In the current study, significantly decreased ISP was reported with FKB327 compared with CCF-RP, which may be due to the citrate buffer that is present in CCF-RP but not in FKB327, as an association between citrate buffer and ISP has been demonstrated previously [9]. Results have shown that a citrate-free formulation of the RP was associated with significantly decreased ISP [29, 30]. Therefore, the results of the current study support previous findings demonstrating an association between a decreased level of ISP and citrate-free formulations.
This study has a number of limitations. The systematic analysis presented requires combining data/events across a number of different studies, which may introduce bias. Moreover, each study used different patients, sites and administration devices such that the results of the systematic analysis may not be as valid as the individual results from each trial. Some of the studies were of short duration, and the concern over pain from a single injection may be different from ongoing pain associated with longer-term administration. The timing of ISP assessment may also limit the conclusions of this analysis based on variability of measurement immediately after injection (Studies 001 and 004) or within 30 minutes after injection (Studies 002 and 003), resulting in the potential for pain resolution within this time frame.
Conclusions
FKB327 (citrate-free formulation adalimumab biosimilar) showed clinically significantly less ISP compared with the CCF-RP.
No statistically significant differences were observed in ISRs or AEs related to ISRs between FKB327 and the CCF-RP or among FKB327 methods of administration. The lower ISP score observed with FKB327 delivered via an AI compared with a vial and RS or a PFS suggests FKB327, especially when delivered via AI, can result in less ISP than the CCF-RP. This is important, because ISRs and ISP can interfere with patients adhering to injectable medications as prescribed.
For patients
Biosimilars are drugs that act in a similar way compared with the reference product but may have small differences in ingredients. Drug ingredients and needle size may affect the amount of injection-site pain that is experienced when the drug is injected into the skin. This paper tested the difference in injection-site pain between the biosimilar drug, FKB327 and the reference product, and differences in pain with a pre-filled syringe, an autoinjector, and a vial/syringe. The study found that patients reported lower pain scores with FKB327 compared with the reference product, and lower pain scores were reported with the autoinjector. These findings mean that receiving FKB327 injections with an autoinjector leads to lower amounts of pain and side effects that may help to make it easier to continue treatment with this drug.
Clinical trials registration
FKB327-001 – EU Clinical Trials, EudraCT No.: 2012-005140-23, protocols.io, registered 12 July 2019, www.protocols.io/view/systemic-analysis-of-injection-site-pain-caused-by-3r2gm8e/abstract FKB327-002 – National Institutes of Health (NIH) US National Library of Medicine, NCT02260791, prospectively registered 29 July 2014, https://clinicaltrials.gov/ct2/show/NCT02260791 FKB327-003 – NIH US National Library of Medicine, NCT02405780, prospectively registered 17 March 2015, https://clinicaltrials.gov/ct2/show/NCT02405780 FKB327-004 – protocols.io, registered 12 July 2019, www.protocols.io/view/systemic-analysis-of-injection-site-pain-caused-by-3r2gm8e/abstract
Funding sources
Funding for the FKB327-001 (EudraCT No.:2012-005140-23), FKB327-002 (NCT02260791), FKB327-003 (NCT02405780), and FKB327-004 studies was sponsored by Fujifilm Kyowa Kirin Biologics Co Ltd. Technical, editorial and medical writing assistance was provided under the direction of the authors by The Lynx Group LLC. Funding for this support was provided by Mylan Inc.
Author contributions
RA, HK, MG: substantial contributions to the conception and design of the work; RA, HK, MB, TY, TI, MG: the acquisition, analysis and interpretation of data; RA, MB: drafted the work or substantively revised it; RA, HK, MB, TY, TI, MG: approved the submitted version of the manuscript. The authors made all content and editorial decisions and received no financial support or other form of compensation related to the development of this manuscript. All authors had final approval of the manuscript and are accountable for all aspects of the work in ensuring the accuracy and integrity of this manuscript. Authors have full control of all primary data and agree to allow the journal to review the data if requested.
Declarations
Ethics approval and consent to participate The studies were conducted in accordance with the Declaration of Helsinki and International Conference on Harmonization Guidelines for Good Clinical Practice. Written informed consent was obtained from all subjects and patients before study entry. Study protocols were reviewed and approved by an independent ethics committee or institutional review board (IRB) for each study centre (protocol no. FKB327-001, EudraCT No.: 2012-005140-23; approved 12 March 2013, by Scotland A Research Ethics Committee; protocol no. FKB327-002, EudraCT No.: 2014-000109-11/NCT02260791, approved 25 November 2014, by United States of America Quorum IRB [central IRB for California sites in US], approval no. 29659; protocol no. FKB327-003, EudraCT No.: 2014-000110-61/NCT02405780, approved 25 November 2014, by United States of America Quorum IRB, approval no. 30276; approval was obtained for each of the study sites – 109 sites in -002 study and 92 sites in -003 study; protocol no. FKB327-004, approved 18 December 2015, by Hakata Clinic IRB).
Competing interests: RA has received research grants and consultant fees from Fujifilm Kyowa Kirin Biologics Co Ltd. RA has received consultant fees from Mylan Inc and has been a paid speaker for the Speakers Bureau of Mylan Inc. HK has nothing to disclose. MB has nothing to disclose. TY received a grant from Fujifilm Kyowa Kirin Biologics Co Ltd during the conduct of this study. TI is an employee of Fujifilm Kyowa Kirin Biologics and reports personal fees from Fujifilm Kyowa Kirin Biologics Co Ltd during the conduct of this study. MG has received consultant fees from Fujifilm Kyowa Kirin Biologics Co Ltd, including for the design of this trial.
Provenance and peer review: Not commissioned; externally peer reviewed.
Authors
Rieke Alten1, MD, PhD Herbert Kellner2, MD Malcolm Boyce3, MD Takuma Yonemura4, MD Takahiro Ito5, MSc Mark C Genovese6, MD
1University Medicine Berlin, Berlin, Germany 2Specialist Practice in Rheumatology and Gastroenterology, Munich, Germany 3Hammersmith Medicines Research, London, UK 4Souseikai Sumida Hospital, Tokyo, Japan 5Fujifilm Kyowa Kirin Biologics, Tokyo, Japan 6Stanford University Medical Center, Palo Alto, CA, USA
References 1. European Medicines Agency. Humira (adalimumab). 2019 [homepage on the Internet]. [cited 2020 Jul 31]. Available from: ww.ema.europa.eu/en/medicines/human/EPAR/humira 2. Abbott Laboratories. HUMIRA (adalimumab) [prescribing information]. North Chicago, IL: AbbVie Inc; 2019. 3. Nakamizo S, Miyachi Y, Kabashima K. Addition of cyclosporine to adalimumab improved psoriasis and adalimumab-induced injection site reaction. Indian J Dermatol. 2014;59(5):522-3. 4. Corominas M, Gastaminza G, Lobera T. Hypersensitivity reactions to biological drugs. J Investig Allergol Clin Immunol. 2014;24(4):212-25. 5. Sator P. Safety and tolerability of adalimumab for the treatment of psoriasis: a review summarizing 15 years of real-life experience. Ther Adv Chronic Dis. 2018;9(8):147-58. 6. Mease PJ. Adalimumab in the treatment of arthritis. Ther Clin Risk Manag. 2007;3(1):133-48. 7. Matsui T, Umetsu R, Kato Y, Hane Y, Sasaoka S, Motooka Y, et al. Age-related trends in injection site reaction incidence induced by the tumor necrosis factor-α (TNF-α) inhibitors etanercept and adalimumab: the Food and Drug Administration adverse event reporting system, 2004-2015. Int J Med Sci. 2017;14(2):102-9. 8. Murdaca G, Spanò F, Puppo F. Selective TNF-α inhibitor-induced injection site reactions. Expert Opin Drug Saf. 2013;12(2):187-93. 9. Laursen T, Hansen B, Fisker S. Pain perception after subcutaneous injections of media containing different buffers. Basic Clin Pharmacol Toxicol. 2006;98(2):218-21. 10. Bolge S, Eldridge H, Doshi D, Ellis L, Roland B, Woelfel J. Patient satisfaction and experience with golimumab, adalimumab, and etanercept for the treatment of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis. 2012 ACR/ARHP Annual Meeting; 9-14 Nov 2012; Washington, D.C. 11. Betegnie AL, Gauchet A, Lehmann A, Grange L, Roustit M, Baudrant M, et al. Why do patients with chronic inflammatory rheumatic diseases discontinue their biologics? An assessment of patients’ adherence using a self-report questionnaire. J Rheumatol. 2016;43(4):724-30. 12. Gely C, Marin L, Gordillo J, Mañosa M, Bertoletti F, Cañete F, et al. N032 Impact of pain due to subcutaneous administration of a biological drug. J Crohns Colitis. 2018;12(1):S582-3. 13. Singh SK, Mahler HC, Hartman C, Stark CA. Are injection site reactions in monoclonal antibody therapies caused by polysorbate excipient degradants? J Pharm Sci. 2018;107(11):2735-41. 14. HULIO (adalimumab-fkjp) [prescribing information]. Morgantown, WV: Mylan Pharmaceuticals Inc; 2020. 15. Puri A, Niewiarowski A, Arai Y, Nomura H, Baird M, Dalrymple I, et al. Pharmacokinetics, safety, tolerability and immunogenicity of FKB327, a new biosimilar medicine of adalimumab/Humira, in healthy subjects. Br J Clin Pharmacol. 2017;83(7):1405-15. 16. Al-Salama ZT. FKB327: an adalimumab biosimilar. BioDrugs. 2019;33(1):113-6. 17. U.S. Food and Drug Administration. Guidance for industry on skin irritation and sensitization testing of generic transdermal drug products. 3 February 2000 [homepage on the Internet]. [cited 2020 Jul 31]. Available from: www.federalregister.gov/documents/2000/02/03/00-2299/guidance-for-industry-on-skin-irritation-and-sensitization-testing-of-generic-transdermal-drug 18. Elgundi Z, Reslan M, Cruz E, Sifniotis V, Kayser V. The state-of-play and future of antibody therapeutics. Adv Drug Deliv Rev. 2017;122:2-19. 19. Kelly AM. Does the clinically significant difference in visual analog scale pain scores vary with gender, age, or cause of pain? Acad Emerg Med. 1998;5(11):1086-90. 20. Powell CV, Kelly AM, Williams A. Determining the minimum clinically significant difference in visual analog pain score for children. Ann Emerg Med. 2001;37(1):28-31. 21. Gandell DL, Bienen EJ, Gudeman J. Mode of injection and treatment adherence: results of a survey characterizing the perspectives of health care providers and US women 18–45 years old. Patient Prefer Adherence. 2019;13:351-61. 22. Rho YH, Rychlewska-Hańczewska A,Śliwowska B, Kim TH. Usability of prefilled syringe and autoinjector for SB4 (an etanercept biosimilar) in patients with rheumatoid arthritis. Adv Ther. 2019;36(9):2287-95. 23. Phillips JT, Fox E, Grainger W, Tuccillo D, Liu S, Deykin A. An open-label, multicenter study to evaluate the safe and effective use of the single-use autoinjector with an Avonex® prefilled syringe in multiple sclerosis subjects. BMC Neurol. 2011;11:126. 24. Freundlich B, Kivitz A, Jaffe JS. Nearly pain-free self-administration of subcutaneous methotrexate with an autoinjector: results of a phase 2 clinical trial in patients with rheumatoid arthritis who have functional limitations. J Clin Rheumatol. 2014;20(5):256-60. 25. Xie L, Zhou S, Wei W, Gill J, Pan C, Baser O. Does pen help? A real-world outcomes study of switching from vial to disposable pen among insulin glargine-treated patients with type 2 diabetes mellitus. Diabetes Technol Ther. 2013;15(3):230-6. 26. Glenski S, Conner J. 29 gauge needles improve patient satisfaction over 27 gauge needles for daily glatiramer acetate injections. Drug Healthc Patient Saf. 2009;1:81-6. 27. Alam M, Geisler A, Sadhwani D, Goyal A, Poon E, Nodzenski M, et al. Effect of needle size on pain perception in patients treated with botulinum toxin type A injections: a randomized clinical trial. JAMA Dermatol. 2015;151(11):1194-9. 28. Beirne PV, Hennessy S, Cadogan SL, Shiely F, Fitzgerald T, MacLeod F. Needle size for vaccination procedures in children and adolescents. Cochrane Database Syst Rev. 2018;8(8):CD010720. 29. Nash P, Vanhoof J, Hall S, Arulmani U, Tarzynski-Potempa R, Unnebrink K, et al. Randomized crossover comparison of injection site pain with 40 mg/0.4 or 0.8 mL formulations of adalimumab in patients with rheumatoid arthritis. Rheumatol Ther. 2016;3(2):257-70. 30. Yoshida T, Otaki Y, Katsuyama N, Seki M, Kubota J. New adalimumab formulation associated with less injection site pain and improved motivation for treatment. Mod Rheumatol. 2019;29(6):949-53.
Author for correspondence: Rieke Alten, MD, PhD, Head of Department of Internal Medicine II, Professor of Medicine, Director of Rheumatology Research Center, Rheumatology, Clinical Immunology, Osteology, Physical Therapy and Sports Medicine, Schlosspark-Klinik Charité, University Medicine Berlin, 2 Heubnerweg, DE-14059 Berlin, Germany
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Introduction: The European Union (EU) and the European Medicines Agency (EMA) have led the development of a regulatory framework for biosimilars since 2004. By end of December 2019, 64 biosimilars of 15 originator biological medicines have a marketing authorization in Europe. Now, for the second time, the Alliance for Safe Biologic Medicines (ASBM) asked European prescribers for their views on the prescribing, adverse drug reaction reporting, automatic substitution and switching of biologicals and biosimilars. Methods: In March 2019, the ASBM surveyed 579 prescribers in France, Germany, Italy, Spain, Switzerland and the UK. Prescribers were asked for their views on authority over prescribing and dispensing of biologicals/biosimilars, reporting biological/biosimilar use and adverse drug reactions (ADR) and switching. There were also questions related to their familiarity with, knowledge of, attitudes to, and beliefs in, biosimilars. Results: Since the previous European prescriber study conducted in 2013, the percentage of respondents considering themselves highly familiar with biosimilar medicines has increased from 76% to 90%. Four out of five prescribers said they are legally required to report ADR that are brought to their attention and they file detailed ADR reports taking 10–20 minutes. Four out of five prescribers feel very strongly about having control over what is prescribed and dispensed to their patients. While highly comfortable prescribing biosimilars to naïve patients, physician comfort level decreased when switching a stable patient to a biosimilar. Comfort level decreased further when prescribers were asked about switching a patient to a biosimilar for non-medical reasons, e.g. cost, and further still if the switch is initiated by a third party. Conclusion: European physicians have increased their familiarity with biosimilars since the 2013 survey. Physicians increasingly believe they should always have control of treatment decisions including the decision to switch to a biosimilar. It was also highlighted that governments should make multiple therapeutic options available through tenders.
Submitted: 9 July 2020; Revised: 9 August 2020; Accepted: 19 August 2020; Published online first: 26 August 2020
Introduction
Healthcare systems across the globe face resource and budget constraints. Biosimilar drug products offer less expensive alternatives to brand-name originator drug products and can thus offer some relief to healthcare costs. Biosimilars are highly similar and have no clinical meaningful differences; but are not identical to originator biologicals. As countries seek to control health costs and expand access to biological therapies, building physician confidence in biosimilars is critical to promoting their use and reaping the cost benefits.
The European Union (EU) and the European Medicines Agency (EMA) have led the development of a regulatory framework for biosimilars. In 2005, EMA established the first biosimilars approval pathway that was distinct from generics approval [1]. Since then, EMA has developed and refined a comprehensive set of regulatory guidelines on which biosimilar applications are reviewed and approved or rejected. By the end of 2019, 58 biosimilars of 15 originator biological medicines have a marketing authorization in Europe [2]. The European biosimilars market is currently the largest in the world, representing approximately 60% of the global biosimilar market and growing consistently year on year [3].
At present, once authorized, EMA applies a ‘same-label’ (generic) approach to biosimilar product labels [4]. However, there are concerns over whether this is sufficient to ensure appropriate drug switching and product traceability. There is ongoing debate about what information is appropriate in the naming and labelling of biosimilars. In the US, FDA released its requirements for the non-proprietary naming of biological products in January 2017 [4]. Prior to this, the Alliance for Safe Biologic Medicines (ASBM) carried out surveys of Australia and EU prescribers and US pharmacist perspectives on the naming of these products. Overall, both groups believed that naming should make biosimilars distinguishable from originator products [5–7]. The ASBM is an organization composed of diverse healthcare groups including patients, physicians and medical innovators. It is funded by its many member partners that are made up of international organizations and companies [8].
The interchangeability of biosimilars is viewed differently in countries across the world. This is particularly marked by the approaches to interchangeability and substitution in the US and Europe [9]. ‘In the US, insurance mandates can result in formulary changes requiring patients to be switched from a reference product to a biosimilar strictly for cost reasons’ . In Europe, automatic substitution of originator biologicals with biosimilars is rare as this practice excludes physicians from decisions regarding the treatment of patients. There have been a number of surveys and workshops carried out across the world (Australia [5], Europe [4, 6], South America [10] and the US [11]) that have asked for prescriber opinions on prescribing practices, naming and labelling of biologicals. In terms of naming, prescribers in Australia, Europe and the US, overall, agreed that there is a need for distinguishable non-proprietary names to be given to all medications. In South America, knowledge about biosimilars varied in different countries surveyed (Argentina, Brazil, Colombia and Mexico) and revealed gaps in understanding and in the use of distinguishable names for biologicals.
In 2019, the ASBM commissioned 15-minute web-based surveys to be carried out by biological prescribers in six Western European countries (France, Germany, Italy, Spain, Switzerland and the UK) to document their perspectives on biological substitution. This survey mirrors their previous European prescriber survey conducted in 2013 [6] (both survey reports can be found at www.safebiologics.org/surveys).
Overall, the 2019 survey showed that awareness of biosimilars in the countries had increased since the 2013 survey. Specifically, more physicians (90%) rated themselves as being ‘Familiar’ or ‘Very familiar’ with biosimilars than did in 2013 (76%). A strong majority of respondents (82%) felt that it is either ‘Very important’ or ‘Critical’ for them to decide which biological medicine is dispensed to their patients, representing a 10% increase over the results of the 2013 survey. Again, a strong majority of respondents (84%) considered authority to prevent a substitution either ‘Very important’ or ‘Critical’ , another 10% increase over the 2013 findings. In 2019, physicians remained uncomfortable with switching a stable patient to a biosimilar for non-medical reasons. Since the 2013 survey, there has also been a sharp increase in physicians who are highly uncomfortable with a non-medical substitution performed by a third party.
It is hoped that the findings of this study may serve as a resource for other countries in developing biosimilar policies that can build physician confidence in biosimilars. Confidence that will increase biosimilar uptake and reduce government expenditures on biological products.
Sample characteristics and methodology
In March 2019, 579 prescribers practising in six specified European countries (France, Germany, Italy, Spain, Switzerland and the UK) completed the 15-minute web-based survey that was administered in the respondents’ native language – French, German, Italian, Spanish, or English. The survey was commissioned by the ASBM and was a refreshed version of that carried out in 2013 [6]. The questionnaires were developed as a collaboration among ASBM management, ASBM membership and Industry Standard Research (ISR) management. No ‘validation’ was conducted as the instruments did not measure higher level ‘constructs’ . They are purely direct measures of opinion and attitude.
Potential respondents were identified in – and recruited from – a large, global, commercial database/panel of healthcare professionals. The response rate was high because people in this database/panel have already indicated a willingness to participate in market research. In addition, their specialties were known prior to recruitment, which decreased the rate of disqualification, as if someone was identified as representing a specialty that did not qualify for the study, they were not invited.
Respondents were paid a stipend for their participation. Stipends ranged from US$37.00 to US$48.00, depending on the specialty.
Prescriber eligibility criteria
Must prescribe biological medicines in their practice
Must practice in France, Germany, Italy, Spain, Switzerland, or UK
Must specialize in one of 10 practice areas: Dermatology, Endocrinology, Gastroenterology, Haematology-Oncology, Immunology, Nephrology, Neurology, Oncology, Ophthalmology, Rheumatology
Must have been in practice for one year or more
Online survey The surveys were administered by ISR. In summary, prescribers were asked to rate:
The importance of retaining sole authority to decide the most suitable biological for their patients.
The importance of retaining the authority to deny/prevent a substitution by indicating “Do Not Substitute” or similar language when prescribing.
Their comfort level with: a) prescribing a biosimilar to a new (treatment-naïve) patient; and b) switching a stable patient from an originator biological to a biosimilar.
Their comfort level with a biosimilar switch for non-medical reasons, e.g. cost, coverage, a) when performed by the physician; and b) when performed by a third party.
The importance of awarding government tenders on originator biologicals and biosimilars to multiple suppliers.
The importance of national tender offers including factors besides price.
ISR provided statistical significance tests by country and practice area for most questions. The information from these tests made it possible to determine which answers were most significant amongst prescribers from different countries and working in different practice areas.
Information on survey participants Participants were sourced from six countries and across 10 therapeutic areas. The detailed breakdown of this information is as follows. Table 1 provides details of the survey sample disposition.
A total of 579 responses were received:
France: 97 (17%)
Germany: 97 (17%)
Italy: 97 (17%)
Spain: 96 (17%)
Switzerland: 95 (17%)
United Kingdom: 97 (17%)
The breakdown of the practitioner’ s primary therapeutic areas is as follows:
The largest group of prescribers (47%) practice in a hospital setting, with the remainder in academic medical centres (23%), private/family practice (18%), multi-specialty clinics (8%), community settings (3%), and other settings (1%).
Respondents’ mean experience level was 15.5 years in practice. Forty per cent of responders had been practising medicine for 11–20 years, 24% for more than 21 years, 23% for 6–10 years, and 13% for 1–5 years.
Seventy-nine per cent of responders said they commonly treat patients who are using biological medicines prescribed by another healthcare provider.
Respondents use different sources to learn about the details of a medicine for prescribing and monitoring, see figure 1.
All data refer only to those who completed the survey. All data were analysed in MS Excel and checked manually.
Results
Familiarity with biosimilars Familiarity with biologicals versus biosimilars When asked about familiarity with biological medicines, 58% of prescribers said they are ‘Very familiar’ , and have a complete understanding of them, compared to 41% who said the same about biosimilars. Thirty-seven per cent of prescribers said they are “Familiar”, with a basic understanding of biologicals, compared to 49% who said the same about biosimilars. And 4% had heard of biologicals but could not define them, compared to 8% who said the same about biosimilars. All prescribers had heard of biologicals whereas 2% of prescribers have not heard of biosimilars.
Since the 2013 European prescribers study, familiarity with biosimilar medicines increased from 76% to 90%; and a prescriber’ s awareness that a biosimilar may be approved for several or all indications of the reference product on the basis of clinical trials in only one of those indications increased from 63% (2013) to 83% (2019.) Strongest familiarity with biosimilars was among prescribers in Italy, Spain and Germany (48%, 47% and 44% are very familiar/have complete understanding). Prescribers in Switzerland had the lowest familiarity with only 31% stating they are very familiar/have complete understanding of biosimilars; 19% of Swiss prescribers either could not define biosimilars or have never heard of biosimilars.
Strongest familiarity with biological medicines was among Rheumatology and Gastrointestinal prescribers (96% and 88% are very familiar/have complete understanding) when compared to the other practice areas. Strongest familiarity of biosimilars was also among Rheumatology, Gastrointestinal and Endocrinology prescribers (70%, 61% and 60% are very familiar/have complete understanding).
Preferred route to familiarity Of the respondents (n = 517) that said they were very familiar/familiar with biosimilar medicines. The top five sources of information were: 1) scientific publications (70%); 2) national medical conferences/symposia (70%); 3) international medical conferences/symposia (61%); 4) self-study (42%); and 5) CME/IME (40%).
The sources varied among the countries. For example, prescribers in the UK became more familiar with biosimilars through self-study (66%) and scientific publications (56%), while in Spain scientific publications (73%) and CME/IME (66%) were the most utilized.
The top five sources to learn about biosimilars among the respondents (n = 62) who had never heard of, nor could define biosimilar medicines were: 1) scientific publications (68%); 2) international medical conferences/symposia (61%); 3) national medical conferences/symposia (55%); 4) CME/IME (37%); and 5) reference product company sponsored education (35%).
There were no significant differences in the preferred method for becoming familiar with biosimilars among practitioners in different countries.
Biosimilar approval awareness Prescribers in Italy (94%) had significantly higher biosimilar approval awareness compared to the rest of the countries. The specialties with the highest biosimilar approval awareness were Rheumatology (96%), Endocrinology (95%), Oncology (94%) and Gastrointestinal (92%) prescribers. All had significantly higher awareness than other specialties.
Adverse drug reaction reporting: mechanism, recording, information required, barriers The survey showed that four out of five prescribers are legally required to report adverse drug reactions (ADRs) that are brought to their attention.
Italian prescribers rated the highest percentage for being required to report ADRs (96%), and French prescribers the lowest (69%). The practice areas in which the highest number of prescribers are required to report ADRs were Oncology (91%) and Immunology (90%).
More than half (54%) of prescribers said they are most likely to report an ADR to the National Competent Authority (NCA). The UK is significantly more likely to report to a combination of the NCA, the Marketing Authorization Holder (MAH), i.e. the manufacturer, and EMA (54%) as opposed to the NCA alone (29%).
ADR report mechanisms, time spent and follow-up Email was utilized by almost half (49%) of prescribers (n = 550) to report ADRs to the NCA or MAH. However, when looking at specific countries, prescribers in Germany (58%) and the UK (52%) had a majority preference for paper. Prescribers in France (57%) and Italy (60%) had a preference for email, while Spain (53%) preferred a web-based tool/app.
Two-thirds (65%) of prescriber respondents said that the amount of time spent on filing a report ranged from 10 to 20 minutes, with 25% requiring less than 10 minutes and 10% requiring more than 20 minutes (average 36 minutes) While prescribers do file detailed reports, the time varies among the specialties. Dermatology (38%) prescribers need less time to file compared to other practice areas, whilst Neurology (19%), Immunology (17%) and Nephrology (14%) prescribers need more than 20 minutes to file the ADR report.
In terms of follow up from the NCA or MAH, 24% of prescribers responded they always receive follow-up, 21% very often, 30% sometimes, 19% rarely and 6% never. Prescribers in Switzerland have one of the highest rates of follow up from reporting entities (Always, 35%) compared to several other countries.
Information included in the ADR reports When ADR reports are filed for a biological medication, 92% of practitioners responded that information about the ADR experienced by the patient are included, 84% include brand name of the biological suspected to have caused the incident, 80% include date and time of report, 72% include the non-proprietary name of the biological suspected to have caused the incident, 69% include batch number of the biological suspected to have caused the incident, including the manufacturer of the product suspected to have been associated with the reaction.
Prescribers in Italy (79%) are better about including batch number in the ADR report; Germany (74%) prescribers are better about including the manufacturer of the product; prescribers in the UK (90%) are better about including date and time.
When asked about how frequently the NCA or MAH follow-up to request the brand name or manufacturer of the product, 55% of prescribers responded either always or very often, 28% said sometimes, while 18% said rarely or never.
Fifty-five per cent of practitioners said that the level of detail required in ADR reports deters them from reporting minor events. When looking at the country specific data, prescribers in France are significantly more deterred from reporting minor events, while those in Italy are significantly less deterred.
Barriers to reporting ADRs Fifty-five per cent of the prescribers responded that the amount of information necessary to report an adverse drug reaction deters them from reporting minor events. France (74%) is significantly more deterred from reporting minor events, while Italy (38%) is significantly less deterred.
More than half (56%) of prescribers responded that reporting infrastructure, e.g. the mechanism of reporting ADRs, was the biggest barrier to accurate reporting; another 20% responded no barriers exist. When looking at the country specific data, prescribers in Spain identified reporting infrastructure (70%) and lack of integration of electronic health records (55%) as barriers to accurate reporting more so than most countries.
Nearly all prescribers responded that they were somewhat confident (62%) or highly confident (36%) in the European pharmacovigilance system’ s ability to accurately identify the specific product at the brand-name level that might be responsible for the ADR. However, prescribers in the UK were less confident in the European pharmacovigilance system than the other countries surveyed, with only 24% reporting they were ‘highly confident’ the system would be able to accurately identify the product responsible.
Frequency of including batch number when reporting adverse events was mixed; 37% always, 27% very often, 20% sometimes, 17 % rarely/never. The survey showed that prescribers in Italy (55%) were best about including batch number (always) when compared to most of other countries. Of the prescribers who said they only included batch number sometimes, rarely, or never, more than half (53%) of prescribers responded that the reason for this was due to not having it available at time of reporting.
Automatic substitution, switching and physician choice A high majority of prescribers (82%) feel very strongly about having control over what is prescribed and dispensed to their patients.
Opinion on sole authority for prescribers Most prescribers agreed that it is either critical or very important (82%) that they had the sole authority, together with their patients, to decide on the most suitable biological medicine for their disease. When looking at each country, it is significantly more critical to have sole authority in deciding medicine for prescribers in Italy (94%), Switzerland (91%) and Germany (84%). When looking at specific fields, it was most important/critical to have sole authority in deciding biological medicine for Immunology (86%), Dermatology (86%) and Ophthalmology (86%) prescribers. It was least important/critical for Haematology-Oncology prescribers, 20% of whom considered it slightly/not important, compared to an average of 2% across all specialties which thought this, see figure 2.
It is significantly more critical to have sole authority in deciding medicine for Immunology, Rheumatology, Dermatology and Endocrinology.
Government tenders Most prescribers stated that they believe it is very important or critical (63%) that government tenders for biosimilars are awarded to multiple suppliers. Prescribers in Spain and the UK, while considering this very important, do not think it is as critical for government tenders to be awarded when compared to the other countries surveyed. Only 7% and 9% considered this ‘critical’ compared to an 18% average across all other respondents.
Most prescribers agreed that it is either critical or very important (83%) that factors besides price to be taken into account in national tender offers, e.g. reliability of supply, patient support services, manufacturer reputation.
Prescriber authority to deny substitution Most prescribers agreed that it is either critical or very important (84%) that, in a situation where substitution by a pharmacist was an option in their country, they have the authority to designate a biological medicine as ‘DISPENSE AS WRITTEN’ or ‘DO NOT SUBSTITUTE’ . It was significantly more critical for those in Switzerland (94%) to have authority to deny substitution for a biological medicine, and least so for those in the UK (73%), compared to those in the other countries. It was significantly less important for Haematology-Oncology prescribers to be able to deny substitution when compared to almost all other practice areas, see figure 3.
Identifying medicines Eighty-five per cent of prescribers said that, when prescribing medicine including biologicals, they identify the medicine in the patient record by brand name. When looking at country and practice area responses, UK (68%) and Oncology (56%) identify medicine in a patient’ s record by brand name significantly less than those in other countries and practice areas, see figure 4.
Forty-three per cent of prescribers responded they rarely or never prescribe biological products by non-proprietary name only. When compared to the other countries, prescribers in Switzerland (40%) are most likely never to use the non-proprietary name of a product. When compared to those in other practice areas, Dermatology (32%) and Rheumatology (28%) prescribers are more likely never to use the non-proprietary name of a product, see figure 5.
When asked about how confident a prescriber can be in their ability to know exactly what product is dispensed to a patient when using a non-proprietary name, 63% were very or somewhat confident, while 38% were slightly confident or not confident at all. Prescribers in Switzerland (26% are not confident at all) noted that they are significantly less confident in knowing what is dispensed when a non-proprietary name is used than those in Italy, Spain and the UK. Prescribers in the fields of Dermatology (55%) and Rheumatology (42%) are significantly less confident in knowing what is dispensed when a non-proprietary name is used compared to those in several other practice areas, see figure 6.
Dispensing in pharmacies When asked about biological products dispensed directly to patients in a pharmacy, 61% of prescribers said that they were either very confident or somewhat confident that, if the pharmacy dispenses a drug that is different from the one that is prescribed (whether it is biosimilar 1, 2, or 3 or even the reference product), they have the ability to identify exactly what drug was dispensed to the patient. Thirty-nine per cent were either slightly confident or not confident at all. Prescribers in the UK (73%) said they are significantly more confident in knowing what is dispensed by pharmacy than those in Germany (49%) and Spain (60%); and those in Switzerland (24% not confident at all) are significantly less confident than several countries. It was shown that Oncology (82%) prescribers are significantly more confident in knowing what is dispensed than those in almost all of the other practice areas, see figure 7.
Eighty-three per cent of prescribers said it was critical or very important to be notified by the pharmacist if a patient has received a biological other than the one prescribed, if the patient was receiving chronic (repeated) treatment. It was shown to be significantly more critical for prescribers in Switzerland (80%) to be notified that a different biological was prescribed than for those in all other surveyed countries. It was also shown that it is significantly more critical for Rheumatology (84%) prescribers to be notified that a different biological was prescribed than those in several other practice areas; and it is significantly less important for Haematology-Oncology prescribers to be notified.
Only 5% of prescribers thought it was totally acceptable for a pharmacist to determine which biological (reference product or biosimilar) to dispense to a patient at the initiation of treatment. Fifty-eight per cent thought this was acceptable if the pharmacist’ s ability to determine the product was agreed to by clinicians in advance, and 37% thought it not acceptable. It was shown to be significantly not acceptable for a pharmacist to make the decision for prescribers in Spain (52%) and Switzerland (51%) when compared to the other countries surveyed. It was shown to be significantly not acceptable for a pharmacist to make decision more so for Rheumatology (60%) and Dermatology (52%) prescribers compared to those in other practice areas, see figure 8.
Prescribing biosimilars and switching Seventy-four per cent of prescribers agreed that the correct definition for a ‘naïve’ patient is: a patient that has never received any biological treatment from this class of medicines. Eighty-four per cent of prescribers said they were very comfortable or somewhat comfortable in prescribing biosimilars to treat naïve patients. Prescribers in France, Germany, Italy, Switzerland and the UK are significantly more comfortable (very) than those in Spain (18%) in prescribing a biosimilar to a naïve patient. Rheumatology (60%) prescribers are more comfortable (very) than those of many other practice areas in prescribing a biosimilar to a naïve patient; Ophthalmology (10%) prescribers are the least comfortable.
Comfort level decreases when asked about switching a stable patient to a biosimilar versus to a naïve patient. While 17% are uncomfortable in prescribing a biosimilar to a naïve patient, see figure 9; twice as many (40%) are uncomfortable with switching a stable patient from an originator to a biosimilar. Spain (54%) prescribers are the least comfortable with switching a stable patient to a biosimilar. Haematology-Oncology prescribers are more comfortable switching a stable patient from an originator to a biosimilar than those in several other practice areas; Ophthalmology and Rheumatology prescribers are less comfortable, see figure 10.
Comfort level decreases further when asked about switching a patient to a biosimilar for non-medical reasons. More than half of prescribers (58%) said they are uncomfortable with switching their patients to a biosimilar for non-medical reasons. Prescribers in France are significantly more comfortable (very) switching a patient to a biosimilar for non-medical reasons than several other countries; prescribers in Italy and Spain are the least comfortable. Haematology-Oncology prescribers are significantly more comfortable (very) switching a patient to a biosimilar for non-medical reasons than those in most other practice areas, see figure 11.
Even more prescribers are uncomfortable (73%) when asked about a third party initiating such a switch. In the UK and France, prescribers were shown to be most comfortable with switching their patients (40% and 35% comfortable, respectively), while in Spain, prescribers are the least comfortable with having a third party make the switch (14%). Haematology-Oncology prescribers were shown to be significantly more comfortable with a third party switching a patient to a biosimilar for non-medical reasons (60% versus an average of 27%) than those in several other practice areas, see figure 12.
Conclusion
In summary, the survey reveals that European physicians have increased their familiarity with biosimilars since last surveyed in 2013. After 13 years of experience with biosimilars in Europe, physicians:
Increasingly consider maintaining physician control of treatment decisions to be highly important
Are more than twice as uncomfortable switching a stable patient to a biosimilar than they are prescribing a biosimilar to a treatment-naïve patient
Remain uncomfortable with switching a patient to a biosimilar for non-medical reasons
Are highly uncomfortable with a non-medical substitution performed by a third party. This figure has increased sharply since the 2013 survey
Consider it highly important for governments to make multiple therapeutic choices available in tenders; and believe these tenders should take into account factors besides price.
Key points of the 2019 European prescribers survey on biosimilar
More than half of prescribers are most likely to report an ADR to the National Competent Authority
Two-thirds of prescribers said amount of time spent on filing a report is 10 to 20 minutes
Prescribers do file detailed reports; this level of detail in turn deters 55% from reporting minor events
More than half of prescribers said reporting infrastructure was the biggest barrier to accurate reporting; another 20% said no barriers exist
Frequency of including batch number is mixed; not having the number available at time of reporting was selected by more than half of prescribers who said sometimes, rarely, or never
Control over prescribing and dispensing – four out of five prescribers feel very strongly about having control over what is prescribed AND dispensed to their patients. Italy prescribers expressed the highest importance in having sole authority to decide the medicine, while France prescribers expressed the least. Switzerland prescribers expressed the highest importance in having the ability to deny a pharmacist’ s substitution, while UK prescribers expressed the least. Having this level of control was most important to Immunology, Rheumatology, Endocrinology and Dermatology prescribers.
Product Name and Pharmacist Control
More than 40% of prescribers said they rarely or never prescribe biological products by non-proprietary name only
More than one-third said confidence would be lacking in knowing exactly what was dispensed to patient if they prescribed a product using non-proprietary name
Four out of five prescribers said it would be critical or very important to be notified by pharmacist that patient received a biological medication other than one they prescribed
Fifty-eight per cent of prescribers said it would be acceptable for a pharmacist to determine which biological to dispense on initiation of treatment, but would require clinician agreement in advance
Prescribe Biosimilar versus Switch to Biosimilar – comfort level decreases when asked about switching a stable patient to a biosimilar versus prescribing a biosimilar to a naïve patient. About 20% are uncomfortable in prescribing a biosimilar to a naïve patient; twice as many (40%) are uncomfortable with switching a stable patient from an originator to a biosimilar. France, Switzerland and UK prescribers are most comfortable with prescribing a biosimilar to a naïve patient, while Spain prescribers are the least comfortable with switching a stable patient to a biosimilar.
Prescriber Switch versus Third-Party Switch – Comfort level decreases when asked about switching a patient to a biosimilar for non-medical reasons. More than half of prescribers (58%) are uncomfortable with switching their patients to a biosimilar for non-medical reasons; this percentage increases to 73% when asked about a third party initiating such a switch. UK and France prescribers are most comfortable with switching their patients, while Spain prescribers are the least comfortable with having a third party make the switch.
Funding sources
The survey study was sponsored by Alliance for Safe Biologic Medicines (ASBM) and administered by Industry Standard Research, LLC.
This paper is funded by the ASBM.
The ASBM is an organization composed of diverse healthcare groups and individuals – from patients to physicians, innovative medical biotechnology companies and others – who are working together to ensure patient safety is at the forefront of the biosimilars policy discussion. The activities of ASBM are funded by its member partners who contribute to ASBM’ s activities. Visit www.SafeBiologics.org for more information.
Competing interests: Dr Madelaine Feldman is the Chairperson of the Alliance for Safe Biologic Medicines. She has participated in advisory boards for Gilead, Lilly, Pfizer and Samsung. Mr Michael S Reilly, Esq, is the Executive Director and employed by Alliance for Safe Biologic Medicines. Mr Reilly served in the US Department of Health and Human Services from 2002–2008.
Provenance and peer review: Not commissioned; externally peer reviewed.
Authors
Madelaine Feldman, MD, FACR Michael S Reilly, Esq
Alliance for Safe Biologic Medicines, PO Box 3691, Arlington, VA 22203, USA
References 1. GaBI Online – Generics and Biosimilars Initiative. EU guidelines for biosimilars. [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2020 Aug 9]. Available from: www.gabionline.net/Guidelines/EU-guidelines-for-biosimilars 2. Bird E. Generics and Biosimilars Initiative Journal (GaBI Journal). 2020;9(1):37-44. doi:10.5639/gabij.2020.0901.007 3. Schneider PJ, Reilly MS. Policy recommendations for a sustainable biosimilars market: lessons from Europe. Generics and Biosimilars Initiative Journal (GaBI Journal). 2020;9(2):76-83. doi:10.5639/gabij.2020.0902.013 4. Jensen AR. Biosimilar product labels in Europe: what information should they contain? Generics and Biosimilars Initiative Journal (GaBI Journal). 2017;6(1):38-40. doi:10.5639/gabij.2017.0601.008 5. Murby SP, Reilly MS. A survey of Australian prescribers’ views on the naming and substitution of biologicals. Generics and Biosimilars Initiative Journal (GaBI Journal). 2017;6(3):107-13. doi:10.5639/gabij.2017.0603.022 6. Dolinar RO, Reilly MS. Biosimilars naming, label transparency and authority of choice – survey findings among European physicians. Generics and Biosimilars Initiative Journal (GaBI Journal). 2014;3(2):58-62. doi:10.5639/gabij.2014.0302.018 7. Schneider PJ, Reilly MS. Naming and labelling of biologicals – the perspective of hospital and retail pharmacists. Generics and Biosimilars Initiative Journal (GaBI Journal). 2016;5(4):151-5. doi:10.5639/gabij.2016.0504.040 8. Safe Biologics. Members partners [homepage on the Internet]. [cited 2020 Aug 9]. Available from: www.safebiologics.org/member-partners/ 9. Derbyshire M. USA and Europe differ in interchangeability of biosimilars. Generics and Biosimilars Initiative Journal (GaBI Journal). 2017;6(4):183-4. doi:10.5639/gabij.2017.0604.039 10. Reilly MS, Gewanter HL. Prescribing practices for biosimilars: questionnaire survey findings from physicians in Argentina, Brazil, Colombia and Mexico. Generics and Biosimilars Initiative Journal (GaBI Journal). 2015;4(4):161-6. doi:10.5639/gabij.2015.0404.036 11. Gewanter HL, Reilly MS. Naming and labelling of biologicals – a survey of US physicians’ perspectives. Generics and Biosimilars Initiative Journal (GaBI Journal). 2017;6(1):7-12. doi:10.5639/gabij.2017.0601.003
Author for correspondence: Michael S Reilly, Esq, Executive Director, Alliance for Safe Biologic Medicines, PO Box 3691, Arlington, VA 22203, USA
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Introduction/Study objective: Needle fear is common among patients with rheumatoid arthritis (RA) who require subcutaneous (SC) injections. The convenience, usability and safety of the etanercept biosimilar YLB113 in an injection pen were evaluated among patients who switched from syringe injection. Methods: Patients with RA who had completed the phase III clinical study of YLB113 in a pre-filled syringe (YLB113-002) were enrolled (n = 35) and received once-weekly SC injections with the injection pen (YLB113 50 mg) for 8 weeks. After 8 weeks, patients completed a qualitative survey evaluating the form and design of the pen, its operability, and patient preference for pen or syringe. Adverse events were evaluated throughout the study. Results: Most patients reported the pen was ‘very easy to grasp’ or ‘easy to grasp.’ The pen was also reported to be easy to operate.The click signalling the start and end of the injection could be heard ‘very well’ or ‘well’ .Similarly, the injection solution check window could be seen by most patients. About three-quarters of respondents preferred the pen over a syringe. The pen was considered easier to use for the following reasons: the body is easy to grasp; the procedure is easy to understand; and the procedure can be performed without anxiety, fear, or tenseness. Conclusion: The majority of these Japanese subjects with RA in the study judged the YLB113 50 mg delivered by injection pen to be easy to use, convenient and well tolerated.
Submitted: 5 June 2020; Revised: 24 July 2020; Accepted: 27 July 2020; Published online first: 7 August 2020
Introduction/Study objective
Needle fear is common among people with chronic conditions who require injections, including patients with rheumatoid arthritis (RA) [1, 2]. Indeed, approximately one in five people has a fear of needles [3, 4]. Patients who are afraid of needles are significantly more likely to avoid medical treatment compared with those who are not afraid of needles [2, 4]. Moreover, many patients with RA are resistant to changing from oral medications, such as methotrexate, to biological disease-modifying antirheumatic drug (bDMARD) injectable medications, even if they have worsening symptoms [5].Injection experience has been cited as a reason for discontinuation of bDMARDs by more than half of patients who stopped biological therapy [6]. Among patients with other diseases requiring long-term injections, e.g. diabetes, the need for injectable medication has also been associated with non-adherence to therapy [7]. Factors associated with fear of injection may be modifiable by self-injection with an injection pen. For example, young adults are significantly more likely to have a fear of injections if they hear a nurse talk about the injection, watch a nurse prepare the syringe, or watch other people receive injections in the clinic [3]. Furthermore, injection pens have been reported to be easier to use, less painful, and associated with better adherence than syringes [8–10]. Reducing patient anxiety and increasing patient confidence have been shown to improve satisfaction levels with self-injection, which may explain why patients with RA prefer subcutaneous (SC) self-injections over intramuscular injections or intravenous infusions administered in a clinic [11–13].
YLB113 is a biosimilar candidate of etanercept that has been evaluated in a phase III trial, which showed that YLB113 has similar efficacy and safety profiles to the originator product [14]. tanercept is a biological drug that treats autoimmune diseases by inhibiting tumour necrosis factor. Etanercept is indicated for the treatment of RA, juvenile RA, psoriatic arthritis, plaque psoriasis, and ankylosing spondylitis [15]. To evaluate the convenience and patient preference for a pen formulation of YLB113, patients in a phase III trial of YLB113 who switched from a pre-filled syringe to an injection pen were surveyed with a questionnaire.
Methods
Study design Patients with RA who completed the phase III clinical study of YLB113 (YL Biologics) in syringe formulation (YLB113-002) were enrolled in the present study. The YLB113-002 study has been described in detail elsewhere [14]. Briefly, 528 patients from Europe, Japan, or India with moderate-to-severe RA receiving concomitant methotrexate were randomly assigned to receive YLB113 (n = 266) or etanercept reference product (Enbrel; n = 262), both of which were administered by pre-filled syringe. After 24 weeks of treatment, the ACR20 response rate (a composite measure defined as ≥ 20% improvement in tender and swollen joint counts and ≥ 20% improvement in three of the following five criteria: patient global assessment, physician global assessment, functional ability measure, visual analogue pain scale, and erythrocyte sedimentation rate or C-reactive protein) was similar between groups: 87.1% for the reference product and 81.3% for YLB113.
A total of 241 Japanese patients completed YLB113-002. Japanese participants were enrolled in the present study in the order of completion, i.e. the first 35 patients who completed and submitted informed consent were enrolled in the present study. Patients submitted written consent to switch from the pre-filled syringe used in YLB113-002 to an injection pen. Patients self-administered once-weekly SC injections with the injection pen (50 mg) for a total of 8 weeks. figure 1 shows a study flow of the cohort.
At the start of the trial, patients were provided with YLB113 pen instructions for use and training regarding proper injection pen use. Participants were instructed to hold the injection pen in the vertical position and were informed about the possibility of insufficient injection. During training, patients simulated injection using an injection pen and a foam pad for practice. The first dose was then self-injected under the direction of a nurse or study collaborator.
Prior to enrolling in the 8-week survey study, participants responded to a survey that evaluated fear of injection, fear of self-injection, and injection pain using a syringe. At the end of the 8-week survey study, participants answered the same questions for the pen device. Patients also completed the self-injection operability and convenience survey at the conclusion of the 8 weeks.
Adverse events were evaluated throughout the study.
This study protocol was reviewed and approved by the YL Biologics Ltd. Clinical Trial Review Committee registration and approval number: YLB-03-2016 (28 June 2016). The Pharmaceuticals and Medical Devices Agency accepted the study protocol on 8 July 2016 (Clinical Trial Number: 28-1652).
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee (YL Biologics Ltd. Clinical Trial Review Committee, registration number YLB-03-2016) and with the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. The ethics committee at each clinical site provided approval for study implementation.
This manuscript does not contain any studies with animals performed by any of the authors.
YLB113 injection The unique YLB113 injection pen device is a pre-filled injection pen of etanercept. The injection pen is cylindrical, about 2 cm in diameter and 14 cm long, see figure 2, with a 27-gauge needle and 0.5 inches of exposed needle. Safety features include a green safety guard around the needle to prevent accidental needle sticks.
See the Appendix in the electronic supplementary materials for the full YLB113 instructions for use. Briefly, the pre-filled pen should be firmly pressed at a 90-degree angle into the skin to begin the injection. An audible click signals the beginning of the injection, and a second audible click signals the end of the injection. After the second click, users are instructed to count slowly to 15 to ensure the injection is complete before moving the pen.
Qualitative operability and convenience survey Prior to the survey study, a formative human factors study of the YLB113 pen was conducted to identify human errors that may occur during self-injection of the device. Overall, the device was found to be easy to use, but many participants expressed concerns about self-injection due to fear of needles and injection pain. Based on the results of this human factors study, a survey was developed to qualitatively evaluate operability and convenience among patients who had previously used syringes to inject etanercept. Survey questions evaluated past self-injection experience, injection pen ease of use, injection pen operability, and preference for the injection pen or the pre-filled syringe. Patient opinions about the pen itself were also solicited in an open-answer format at the end of the survey. See the Appendix in the electronic supplementary materials for the full operability and convenience survey administered to patients.
Results
A total of 10 men and 25 women were enrolled in the study, see Table 1. No differences between men and women were reported for ACR (American College of Rheumatology) Global Functional Status or Disease Activity Score in 28 joints. The mean (standard deviation) age was 53.8 (11.2) years. The majority of patients (91.4%) were experienced with self-injection with a pre-filled syringe prior to the start of the injection pen study. The remainder received their injections from a caregiver or healthcare provider throughout YLB113-002. Two patients performed self-injection for the first time during the injection pen study, and one patient elected to have a caregiver administer the injection throughout the study.
The form and design of the injection pen were evaluated in terms of appearance and ease of grip. Most patients reported finding the pen easy or very easy to grasp in terms of diameter, length, and overall body, see Table 2.
The operability of the injection pen was evaluated, see Table 3. In general, patients reported that the clicking feature that signals the start and end of the injection could be heard very well or well. Similarly, most patients reported that the injection solution check window could be seen well or could be seen. Opinions regarding the duration of injection were varied, with one-third of patients reporting the duration was ‘just right’ , and others reporting it was long or short. A total of 5 (14.3%) patients reported difficulty with pressing the tip of the injection pen vertically to the skin. Of these 5 patients, 4 reported that they had experienced injection spillage at least once. Spillage was defined as drug that was not injected into the patient and either pooled on the skin at or near the injection site or spilled from the needle as a result of incomplete injection.
As seen in figure 3, self-reported fear and pain decreased with use of the injection pen compared with use of the pre-filled syringe. At the start of the survey, 35 patients (100%) reported they found injecting with a syringe either ‘very scary’ or ‘a little scary’ . At the end of the survey, 28 patients (80.0%) reported they felt no fear using the injection pen, whereas five patients (4.7%) found the injection pen ‘a little scary’ . Fear of self-injection was also reduced, with 30 patients (85.6%) reporting self-injection was ‘very scary’ or ‘a little scary’ with the syringe, which decreased to one patient (2.9%) and five patients (14.3%) reporting that the injection pen was ‘very scary’ or ‘a little scary’ , respectively. Differences between syringe and pen injection were significantly different for all measurements, i.e. fear of needle for injection, fear of self-injection, and feeling of pain at injection; p < 0.001 Wilcoxon rank sum test.
When patients were asked to compare their experiences with the injection pen and syringe in the qualitative operability and convenience survey, most self-reported that their fear and anxiety ‘decreased’ or ‘very much decreased’ upon switching from syringe to injection pen, see Table 4. However, 42.9% of patients reported no change in a tense feeling related to self-injection. About three-quarters of respondents preferred the injection pen to a syringe for ease of use. The reasons given for the ease of use of the injection pen included that the body was easy to grasp; the procedure was easy to understand; and the procedure was performed without anxiety, fear, or tenseness. Furthermore, most patients found the injection pen easier to use and planned to use the injection pen over the syringe.
Patients were asked for their opinions and requests for improvement for the injection pen. A total of five patients reported they would prefer reduced pain, and three reported a desire for a different infusion rate. Another common theme among patients was concern regarding the lack of control over injection duration and flow rate, which led to worry about the inability to stop the injection if they felt pain. Two women reported that they would like a smaller-sized injection pen.
No pen defects or treatment discontinuations occurred during the study. Among the 35 patients, 15 (42.9%) reported adverse events associated with the use of YLB113. The most common adverse events were infections (17.1%). Adverse events with a potential causal relationship to the study drug were reported in two patients: injection-site haemorrhage and hydronephrosis. One serious adverse event reported (otitis media) was deemed unrelated to the study drug.
Discussion
In this operability and convenience survey of patients with RA, 74% of participants preferred self-injecting YLB113 with an injection pen over a pre-filled syringe. Participants reported that use of the injection pen was easier, more comfortable, and less fear-inducing than use of the syringe. A minority of patients (14%), however, reported that the injection pen caused pain, and, because the injection pen procedure is not adjustable, they would prefer to use a syringe. Pain may be caused by a variety of factors, including the osmotic pressure of preparation, injection needle, device, infusion rate, and duration of injection.
In addition, patients reported that the injection pen was easy to grasp and easy to use. Although most patients could hear the first and second clicks, a small proportion (8.5%) was unable to hear them, suggesting that users with hearing difficulty may be unable to hear the clicks. Redundant features, such as the pink colour in the viewfinder, are key to ensuring all patients can confirm complete injection. Except for one patient who ‘could not say’ , all patients could see the pink plunger in the viewfinder window, indicating that even those patients with hearing difficulties can administer complete doses. This is important for the RA patient population, among whom hearing loss is common [16].
The benefits of an injection pen relative to a pre-filled syringe may be in part due to the ease of use of the device compared with a pre-filled syringe. Whereas administration of medication via a syringe requires the user to simultaneously press the device into the skin and depress a plunger, the YLB113 injection pen only requires the user to firmly press the cartridge to the injection site. This is relevant in patients with RA, among whom manual dexterity and grip strength may be impaired [17]. Furthermore, past studies have shown that patients with RA may prefer a button-free autoinjector, similar to the design of the YLB113 pen [18]. Other features that contribute to the ease of use of the YLB113 injection pen include the comfortable barrel size, the ridged cap for improved grasp, and the moderate level of force required to initiate injection. finally, the cost of YLB113 is comparable to that of other etanercept formulations, and the cost of the injection pen is similar to that of a pre-filled syringe, further supporting use of the YLB113 pen.
The results of this study are in line with past prospective, controlled trials of the use of injection pens compared with the use of syringes. Patients with RA reported a preference for methotrexate delivered by an autoinjector instead of a pre-filled syringe regarding ease of use, acceptability and satisfaction [19]. These results have also translated to other chronic conditions that may require injections. For example, patients with ulcerative colitis found a golimumab autoinjector extremely easy or easy to use at a higher rate than golimumab injected via a pre-filled syringe (94.5% vs 73.6%) [20]. Furthermore, patients with ulcerative colitis reported moderate discomfort at a higher rate when using a pre-filled syringe (20.9%) than when using an autoinjector (5.5%) [20]. Similar results have been reported among patients with infertility and chronic kidney disease [21, 22].
Several limitations have been identified in this study. This is an observational study that did not have a control arm of patients receiving an injection via pre-filled syringe. However, all enrolled patients had previously received injection with a pre-filled syringe in a phase III trial, and therefore had experience with syringe injections of etanercept. Another limitation in this study is the self-reported nature of the results, which can introduce recall bias. finally, a small number of patients were included in this study, and although several patients with severe disability were enrolled, the results may not be generalizable to the RA population as a whole. Additional studies in larger populations would be beneficial to better elucidate patient opinions of injection pen operability and convenience. Despite the limitations of the study, it is of note that the fear of injection decreased substantially among pen users who had previously used pre-filled syringes, suggesting that the YLB113 injection pen may be preferred among end users.
Conclusion
In conclusion, the results of a survey of 35 Japanese patients with RA suggest that the YLB113 injection pen was well tolerated and easy to use; and was preferred for etanercept injections.>
Clinical trials registration
YL Biologics Ltd. Clinical Trial Review Committee registration and approval number: YLB-03-2016 (28 June 2016) Pharmaceuticals and Medical Devices Agency Clinical Trial Number: 28-1652 (8 July 2016)
Acknowledgements
This study was conducted as a part of the phase III study conducted in Japan, which was controlled and funded by YL Biologics Ltd. TY, AS, IM, and TF are the clinical investigators who contributed to the clinical study in the hospitals. TH is responsible for the operation and is the main sponsor of the study, joined by the co-authors.
The authors would like to thank and acknowledge the following hospitals that participated in this study:
International Goodwill Hospital, Japan
Honjo Rheumatism Clinic, Japan
Suga Orthopedic Hospital, Japan
Kumamoto Shinto General Hospital, Japan
Fujimori Clinic, Japan
Rabbit Clinic, Japan
Chikamori Hospital, Japan
Kai Clinic, Japan
The authors would like to acknowledge YL Biologics Ltd for the clinical operations. YLB is the joint venture company between Yoshindo and Lupin, and Lupin contributed to its operation indirectly.
The YLB statistician team conducted the statistical analysis of the data and was supported by EPS.
The authors would like to thank the patients that participated in this study.
Funding sources
Funding for the phase III pen usability study, YLB113-003, was provided by YL Biologics Ltd. Editorial assistance was provided under the direction of the authors by The Lynx Group LLC. Funding support for editorial assistance was provided by YL Biologics Ltd.
Authorship
All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this manuscript, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published. Toshihiko Hibino, Tomohiko Yoshida, Akira Sagawa, Ikuko Masuda, and Takaaki Fukuda made substantial contributions to the conception or design of the manuscript, or the acquisition, analysis, or interpretation of data for the manuscript, and all authors were involved in drafting the manuscript or revising it critically for important intellectual content. The authors were fully responsible for all content and editorial decisions; and received no financial support or other form of compensation related to the development of this manuscript. All authors had final approval of the manuscript and are accountable for all aspects of the work in ensuring the accuracy and integrity of this manuscript.
Compliance with ethics guidelines
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee (YL Biologics Ltd. Clinical Trial Review Committee, registration number YLB-03-2016) and with the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. The ethics committee at each clinical site provided approval for study implementation.
This manuscript is based on previously conducted studies and does not contain any studies with human participants or animals performed by any of the authors.
Data availability
The datasets generated during and or analysed during the current study are available from the corresponding author at reasonable request.
Competing interests: Tomohiko Yoshida and Akira Sagawa declare no conflicts of interest. Ikuko Masuda has been a paid speaker for Teijin Pharma Ltd. Takaaki Fukuda has received consultant fees from YL Biologics Limited and has been a paid speaker for the following: Chugai Pharmaceutical, Takeda Pharmaceutical, Tanabe-Mitsubishi Pharmaceutical, Eisai Pharmaceutical, AbbVie Pharmaceutical, Astellas Pharmaceutical, AYUMI Pharmaceutical, Teijin Pharma Ltd., and Asahi Kasei Pharma. Toshihiko Hibino is an employee of YL Biologics Ltd and reports personal fees from YL Biologics Ltd during the conduct of this study.
Provenance and peer review: Not commissioned; externally peer reviewed.
1YL Biologics Limited, Tokyo, Japan 2Setagaya Rheumatology Clinic, Tokyo, Japan 3Sagawa Akira Rheumatology Clinic, Sapporo, Japan 4Jujo Takeda Rehabilitation Hospital, Kyoto, Japan 5Koga Hospital 21, Kurume, Japan
References 1. Smolen JS, Aletaha D, McInnes IB. Rheumatoid arthritis. Lancet. 2016;388 (10055):2023-38. Erratum in Department of Error. 2. McLenon J, Rogers MAM. The fear of needles: a systematic review and meta-analysis. J Adv Nurs. 2019;75(1):30-42. 3. Nir Y, Paz A, Sabo E, et al. Fear of injections in young adults: prevalence and associations. Am J Trop Med Hyg. 2003;68(3):341-4. 4. Wright S, Yelland M, Heathcote K, et al. Fear of needles—nature and prevalence in general practice. Aust Fam Physician. 2009;38(3):172-6. 5. Wolfe F, Michaud K. Resistance of rheumatoid arthritis patients to changing therapy: discordance between disease activity and patients’ treatment choices. Arthritis Rheum. 2007;56(7):2135-42. 6. Bolge SC, Goren A, Tandon N. Reasons for discontinuation of subcutaneous biologic therapy in the treatment of rheumatoid arthritis: a patient perspective. Patient Prefer Adherence. 2015;9:121-31. 7. Davies MJ, Gagliardino JJ, Gray LJ, Khunti K, Mohan V, Hughes R. Real-world factors affecting adherence to insulin therapy in patients with Type 1 or Type 2 diabetes mellitus: a systematic review. Diabet Med. 2013;30(5):512-24. 8. Kivitz A, Cohen S, Dowd JE, Edwards W, Thakker S, Wellborne FR, et al. Clinical assessment of pain, tolerability, and preference of an autoinjection pen versus a prefilled syringe for patient self-administration of the fully human, monoclonal antibody adalimumab: the TOUCH trial. Clin Ther. 2006;28(10):1619-29. 9. Slabaugh SL, Bouchard JR, Li Y, Baltz JC, Meah YA, Moretz DC. Characteristics relating to adherence and persistence to basal insulin regimens among elderly insulin-naïve patients with type 2 diabetes: pre-filled pens versus vials/syringes. Adv Ther. 2015;32(12):1206-21. 10. Miao R, Wei W, Lin J, Xie L, Baser O. Does device make any difference? A real-world retrospective study of insulin treatment among elderly patients with type 2 diabetes. J Diabetes Sci Technol. 2014;8(1):150-8. 11. Keininger D, Coteur G. Assessment of self-injection experience in patients with rheumatoid arthritis: psychometric validation of the Self-Injection Assessment Questionnaire (SIAQ). Health Qual Life Outcomes. 2011;9:2. 12. Fraenkel L, Bogardus S, Concato J, Felson DT, Wittink DR. Patient preferences for treatment of rheumatoid arthritis. Ann Rheum Dis. 2004;63(11):1372-8. 13. Louder AM, Singh A, Saverno K, Cappelleri JC, Aten AJ, Koenig AS, et al. Patient preferences regarding rheumatoid arthritis therapies: a conjoint analysis. Am Health Drug Benefits. 2016;9(2):84-93. 14. Yamanaka H, Kamatani N, Tanaka Y, Hibino T, Drescher E, Sánchez-Bursón J, et al. A comparative study to assess the efficacy, safety, and immunogenicity of YLB113 and the etanercept reference product for the treatment of patients with rheumatoid arthritis. Rheumatol Ther. 2020;7(1):149-63. 15. Enbrel (etanercept) [package insert]. Thousand Oaks, CA: Amgen; 2017. 16. Murdin L, Patel S, Walmsley J, Yeoh LH. Hearing difficulties are common in patients with rheumatoid arthritis. Clin Rheumatol. 2008;27(5):637-40. 17. Palamar D, Er G, Terlemez R, Ustun I, Can G, Saridogan M. Disease activity, handgrip strengths, and hand dexterity in patients with rheumatoid arthritis. Clin Rheumatol. 2017;36(10):2201-08. 18. Thakur K, Biberger A, Handrich A, Rezk MF. Patient perceptions and preferences of two etanercept autoinjectors for rheumatoid arthritis: findings from a patient survey in Europe. Rheumatol Ther. 2016;3(2):245-56. 19. Demary W, Schwenke H, Rockwitz K, et al. Subcutaneously administered methotrexate for rheumatoid arthritis, by prefilled syringes versus prefilled pens: patient preference and comparison of the self-injection experience. Patient Prefer Adherence. 2014;8:1061-71. 20. Vermeire S, D’ heygere F, Nakad A, Franchimont D, Fontaine F, Louis E, et al. Preference for a prefilled syringe or an auto-injection device for delivering golimumab in patients with moderate-to-severe ulcerative colitis: a randomized crossover study. Patient Prefer Adherence. 2018;12:1193-202. 21. Welcker JT, Nawroth F, Bilger W. Patient evaluation of the use of follitropin alfa in a prefilled ready-to-use injection pen in assisted reproductive technology: an observational study. Reprod Biol Endocrinol. 2010;8:111. 22. Lim WH, Chan D, Boudville N, Pellicano S, Herson H, Moody H, et al. Patients’ perceptions of subcutaneous delivery of darbepoetin alfa by autoinjector prefilled pen versus prefilled syringe: a randomized, crossover study. Clin Ther. 2012;34(9):1948-53.
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Introduction: Many countries have introduced policies and strategies to limit pharmaceutical expenditures. These include pharmaceutical pricing policies and related strategies to control medicine prices and to ensure appropriate and stable prices. The aim of this study was to provide an overview of the current pharmaceutical pricing policy for medicines in Saudi Arabia and to provide an evaluation of the impact of this policy on medicine prices. Methods: A description of the current pharmaceutical policy is presented by reviewing the current official documents and regulations related to pharmaceutical pricing in Saudi Arabia. A price comparison between the original brand medicines and their generic versions was conducted for the top six selling medicines in Saudi Arabia during the period of 2010–2015. Results: The findings showed that Saudi pharmaceutical pricing policy takes into consideration several factors including an international price benchmark, internal price referencing, and the price of the medicine in the country of origin when determining medicine prices. Based on this policy, there were large differences in the prices of generic medicines compared to original brand medicines. The generic medicine to original brand medicine price ratio was 0.87–0.30. However, the price of the first generic medicine was close to the price of original brand medicine, with the first generic medicine-to-original brand medicine price ratio was 0.87–0.81. In this study, there were large differences in the prices of generic medicines for the same molecule. In fact, price ratio among the generic medicines for the same molecule was between 0.96 and 0.18. However, some generic medicines imported from high income countries were cheaper than the medicines manufactured locally or manufactured in other countries in the Middle East. Conclusion: Medicine prices are strictly controlled through the pharmaceutical pricing policy in Saudi Arabia. Overall, the current policy has resulted in significant price differences among medicines, including medicines of the same molecule. Due to this large difference, the cost savings will depend on the product prescribed or procured by the health organization.
Submitted: 1 October 2019; Revised: 23 January 2020; Accepted: 6 February 2020; Published online first: 19 February 2020
Introduction
Healthcare in Saudi Arabia is provided via a dual system, i.e. public and private sector. Approximately three quarters of the healthcare services are currently provided by the public sector. However, the private healthcare sector has grown in recent years and is now considered an essential component of the Saudi healthcare system [1–3]. The public sector is funded mainly by the government budget while the private sector is financed by the cooperative health insurance schemes and out-of-pocket payments [1, 2]. The total healthcare expenditure is steadily increasing from US$23.641 billion in 2011 to US$40.657 billion in 2018 (66% of the total expenditure is currently funded by the governmental budget) [4, 5]. Regarding the Saudi pharmaceutical sector, it depends heavily on imported pharmaceuticals from the US, Europe and some other the Gulf Cooperation Council (GCC) countries [1, 5]. The local pharmaceutical companies produce approximately one quarter of the pharmaceuticals in the Saudi pharmaceutical market [1]. However, more initiatives and investment have started in recent years to stimulate the pharmaceutical production as part of a strategic plan to produce at least 40% of all medicines locally on the long term [1, 5].
Pharmaceutical expenditures make up a large component of overall health expenditures [6–21], representing approximately 20%–60% of the health expenditures in low- and middle-income countries (LMICs) and approximately 18% of the health expenditures in the Organisation for Economic Co-operation and Development (OECD) countries [6]. In Saudi Arabia, pharmaceutical expenditures represented 19.4% of the total health expenditures in 2018 [5]. Moreover, similar to many other countries, this has steadily increased in recent years. For example, pharmaceutical expenditure increased from US$4.894 billion in 2011 to US$7.897 billion in 2018 [4, 5]. The rise in pharmaceutical expenditure can be attributed to many factors. These factors include the increase in the prevalence of diseases, e.g. chronic diseases, the increase in risk factors associated with these diseases, ageing populations, changes in treatment goals (i.e. stricter therapeutic targets), the introduction/early adoption of expensive medicines/new medicines, e.g. biotechnology medicines, anticancer agents, and immunomodulating agents, growth in medicine volumes, and increasing patient expectations [10, 14–18, 22–26].
In view of this tremendous increase in expenditure, which threatens the sustainability of healthcare systems, many countries have introduced strategies and policies, including pharmaceutical pricing policies, to control medicine prices, to ensure medicine affordability and accessibility, to ensure price stability, to promote innovation, and to maintain pharmaceutical production [12, 15, 22, 23, 27–31]. Globally, in terms of the pricing of medicines, several strategies are used, including external price referencing (also called international price benchmark/referencing), internal price referencing, value-based pricing, tendering and negotiations, and special pricing agreements [11, 32]. External price referencing refers to the practice of determining the price of a medicine in a given country by considering the prices of the medicine in other countries in which the product is marketed. Internal price referencing refers to the practice of determining the price of a medicine by considering the prices of its identical, similar, or therapeutically equivalent medicines within the same country. Value-based pricing is used to determine the prices of new medicines based on the therapeutic value of the medicine. This is commonly evaluated through heath technology assessment (HTA) or pharmacoeconomic evaluations, such as cost-effectiveness analysis, cost minimization, and cost–benefit analysis [11, 32]. In tendering procedures, the pharmaceutical companies and manufacturers submit quotations for a particular contract in a competitive bidding process. Then, the company or manufacturer that offers the best bid wins the tender based on the specified criteria [11, 22]. As a pricing strategy, special pricing agreements (also called innovative agreements or managed entry agreements) are adopted by some countries such as Australia, France, Germany, New Zealand, Spain, Taiwan, Thailand and the UK [11, 33]. These agreements are used to facilitate the entry and funding of some new medicines, especially when it is challenging to determine the prices of newly launched medicines because of the uncertainty of their future effectiveness and the value that the medicine will offer in real life situations, beyond just clinical trials [33].
In Saudi Arabia, historically, medicine prices have been determined by the Ministry of Health. Currently, the Saudi Food and Drug Authority (FDA), established in 2003, is the national regulatory body responsible for the registration and approval of medicines, including the pricing of medicines [1]. In Saudi Arabia, according to Pharmaceutical Institutions, and Product Law, retail pharmaceutical prices must be officially approved before marketing any pharmaceutical product [34, 35]. Currently, medicine prices are determined based on the pharmaceutical pricing policy approved by the Saudi FDA. Therefore, the aim of this article was to provide an overview of the current pharmaceutical pricing policy of medicines in Saudi Arabia and to provide an evaluation of the impact of this policy on medicine prices, including both the original brand medicines and generic medicines.
An overview of pharmaceutical pricing policy
Pharmaceutical pricing policy Medicine prices are determined according to pharmaceutical pricing rules and policies, which were approved by the Saudi FDA and have been implemented since November 2011 [36]. The key features of this policy are as follows:
General considerations: In general, when determining the prices of medicines, according to pharmaceutical pricing rules and policies, there are nine factors/criteria that need to be considered, see Table 1.
Pricing of original brand medicines:
Price deduction of the original brand medicine by 20% upon registration of the first equivalent generic medicine.
If the original brand is manufactured locally under license agreement with the license holding company, it will be given the same registered price as the imported original brand. Once the first generic medicine is registered, there will be a 20% reduction.
If the original brand is manufactured by a local manufacturer with license agreement with the license holding company as a second brand, it will be given the same price as the original brand during the patent protection period, and after patent expiration the second local brand will be treated as the first generic medicine in terms of pricing.
Pricing of generic medicines:
Generic medicines are priced by taking into consideration the criteria as stipulated in Table 1.
The first registered generic medicines will be priced at least 35% lower than the price of original brand medicine.
The second registered generic medicine will be priced 10% lower than the set price of the first registered generic medicine. Similarly, the third generic medicine will be priced at least 10% lower than the second registered generic medicine. This is also the case for the fourth generic medicine, where its price will be set at least 10% lower than the third registered generic medicine.
From the fourth generic medicine onward, the price may be fixed without further reductions.
Regulating mark-ups in the pharmaceutical supply chain Mark-ups are determined by Article 13 of the Pharmaceutical Institutions and Products Law, as summarized in Table 2 [34, 35]:
Methods
A price comparison between the original brand medicine, i.e. innovator’s product, and its generic versions was conducted. The analysis was performed for prescription medicines, i.e. active ingredients, in which their products were listed in the top 10 products sold in Saudi Arabia during the period of 2010–2015 [37]. These medicines included diclofenac (three products), amoxicillin/clavulanic acid (two products), metformin/sitagliptin, esomeprazole, atorvastatin, pantoprazole, and tadalafil. In this study, no comparison was attempted for metformin/sitagliptin since it is currently available only as an innovator’s product. To ensure the accuracy of the comparisons, only medicines of the same properties were included [38]. The products compared had to be in the same dosage form, with the same strength and the same package size. In addition, they had to be the same in terms of other characteristics that could affect the price, e.g. film coating. Also, the same package size was considered since medicines in retail community pharmacies usually sell products in their original packages. Moreover, only products that were currently marketed in the country were considered, i.e. products that were not currently marketed or that were suspended or withdrawn by the Marketing Authorisation Holder (MAH) were excluded.
Descriptive comparisons of medicine prices were made based on the official prices of medicines, i.e. retail prices for consumers. The medicine prices were obtained from Saudi FDA’s official list of registered medicines and herbal products (available at https://www.sfda.gov.sa/en/drug/search/Pages/default.aspx) [39].
The study calculated the absolute price difference between the original brand medicine and the generic medicine in Saudi Arabian Riyals (SAR) and it calculated the generics to original brand medicine price ratio. Similarly, among generic medicines, the absolute price difference between the highest price generic medicine and other generic medicines and the price ratio of the highest price generic medicine to other generic medicines of the same molecule were calculated [23].
Results
The study compared the prices of the top selling medicines in Saudi Arabia, including six different medicines. Overall, there were significant differences in the prices of the generic medicines compared to the original brand products. The price ratio of the generic medicines to the original brand medicine was 0.87–0.30. The price of the first generic medicine was close to the price of original brand medicine, where the first generic medicine to original brand medicine price ratio was 0.87–0.81. In this study, there were significant differences in the prices of the generic medicines for the same molecule. In fact, price ratio among the generic medicines for the same molecule was between 0.96 and 0.18. In addition, some generic medicines imported from high income countries were cheaper than the medicines manufactured locally or from other countries within the Middle East. The price comparisons for each medicine are presented in Figure 1.
There was only one generic version of esomeprazole during the study period. The original brand of atorvastatin is currently not marketed; hence, the prices for its generic versions were compared to the first registered generic version.
Diclofenac As shown in Table 3, the price comparison was conducted for diclofenac sodium (50 mg tablets), available in a package size of 20 tablets. The generic medicine to original brand medicine price ratio was 0.87–0.31. In addition, there was a large variation among the prices of the generic versions of diclofenac, where the generic medicine to generic medicine price ratio was 0.9–0.35.
Amoxicillin/clavulanic acid As shown in Table 4, the price comparison was conducted for amoxicillin/clavulanic acid (625 mg tablets), available in a package size of 20 tablets. The generic medicine to original brand medicine price ratio was 0.86–0.31. In addition, there was a large variation among the prices of the generic versions of amoxicillin/clavulanic acid, with the generic medicine to generic medicine price ratio was 0.96–0.36.
Esomeprazole As shown in Table 5, the price comparison was conducted for esomeprazole (40 mg) gastro-resistant coated tablets, available in a package size of 28 tablets. There was only one generic version registered in the same dosage form. The price ratio of generic medicine to the original brand medicine was 0.81.
Atorvastatin As shown in Table 6, the price comparison was conducted for atorvastatin (40 mg) film-coated tablets, available in a package size of 30 tablets. The original brand medicine (Lipitor®) is currently not marketed in Saudi Arabia. Hence, the price comparison was conducted among its generic versions that are currently registered in Saudi Arabia. There was a large variation among the prices of the generic versions of atorvastatin, with the generic medicine to generic medicine price ratio was 0.87–0.18.
Pantoprazole As shown in Table 7, the price comparison was conducted for pantoprazole (40 mg) gastro-resistant, coated tablets, available in a package size of 30 tablets. The generic medicine to original brand medicine price ratio was 0.87–0.46. In addition, there was a large variation among the prices of the generic versions of pantoprazole, where the generic medicine to generic medicine price ratio was 0.84–0.53.
Tadalafil As shown in Table 8, the price comparison was conducted for tadalafil (20 mg) tablets, available in a package size of four tablets. The generic medicine to original brand medicine price ratio was 0.81–0.58. In addition, there was a large variation among the prices of the generic versions of tadalafil, with the generic medicine to generic medicine price ratio was 0.9–0.71.
Discussion
The current approach adopted for medicine pricing is the ‘prescriptive pricing approach’ for both original brand medicines and generic medicines. In this approach, health authorities or regulators mandate price reductions that are necessary for the reimbursement price or for determining the price [15, 29]. In addition, a generic price link policy was adopted in Saudi Arabia. In this policy, the first generic medicine and subsequent generic medicines are priced lower than the original brand medicine. This policy has been implemented in many European countries, such as Austria, Belgium, Switzerland, Germany, Estonia, Finland, France and Ireland [32]. However, the percentage of price reductions at which generic medicines must be priced lower than the original brand medicine, as well as the additional steps, vary widely between countries [32]. Moreover, in Saudi Arabia the generic medicines are priced according to the order of registration, and the subsequent generic medicines are priced at least 10% lower than the product registered earlier.
Currently, the price reduction of the original brand medicine upon registration of the first generic medicine is 20%. The first generic medicine is priced 35% lower than the pre-patent price of the original brand medicine, with subsequent generic medicines priced at least 10% lower, until the fourth generic medicine. This approach has been adopted by several countries, with differences in the percentage of the reductions. For example, in South Korea, upon expiration of the patent, the price of the original brand medicine is reduced by 30%. The generic medicine will be priced 15% lower than the original brand medicine price after the reduction. After one year, there is an additional 10% reduction in the price of the medicine, and both the original brand medicine and the generic medicine are priced at the same level, i.e. 53.55% of the pre-patent price [12, 27, 40]. In Egypt, the original brand medicine price is fixed by selecting the lowest price in the region where the medicine is marketed. The first five generic medicines are priced 35% lower than the innovator’s medicine, while the subsequent generic medicines will be priced 40% lower than the innovator’s product. However, imported generic medicines with high technological features are priced 30%–35% lower than the innovator’s product [41]. In Australia, a 16% reduction in price is made when the first generic medicine is added to the national scheme. Subsequent reductions are made based on a price-disclosure policy. In this policy, which is based on the actual selling price, i.e. ex-factory price, a weighted, one-year average, disclosed price (WADP) is calculated. Accordingly, a price reduction is made if the current ex-factory price is higher than 10% of the WADP (i.e. the price will be reduced to the level of the WADP) [16, 27]. In Europe, particularly France, the first generic medicine is required to be at least 55% lower than the price of the original brand medicine to be reimbursed. In addition, the prices of off-patent medicines are required to be reduced by 15%–19% upon registration of the 1st generic medicine [14, 42]. In Norway, a stepped price model has been adopted. In this model, the price of the prescription medicine is reduced in a stepwise manner after patent expiration of the innovator product. The price reductions depend on the annual sales of the original brand medicine before generic competition, as well the time of generic competition establishment. In the first step (at the time of generic competition establishment), the price is reduced by 35%. This is followed by further reductions in the second (after 6 months) and third steps (18 months or more), which could be a 90% reduction in some medicines, depending on the sales [43].
The current pricing policy in Saudi Arabia has led to major differences in the prices of medicines. However, the price of the first generic medicine is relatively close to the post-patent price of the original brand medicine. In fact, the first generic medicine to original brand medicine ratio was only between 0.87–0.81. However, the price difference between the other subsequent generic versions and the original brand medicine varies widely, but generally it is considered large. The price ratio between the lowest priced medicine and its original brand medicine was 0.58–0.30. The overall generic medicine to original brand medicine price ratio was 0.87–0.30. By comparison, the study by Zeng (2013) reported that in China the difference was 0.34 and 0.98 [23]. In the current study, large variations were noted among the generic medicines of the same molecule, with a generic medicine to generic medicine price ratio of 0.96–0.18. Hence, in terms of pricing, three categories of generic medicines can be noted – the highest priced, moderately priced, and lowest priced generic medicines. In addition, the prices of some local products are higher than the imported generic medicines from some high-income countries.
In fact, in addition to the initial reductions in the prices of medicines, there are different subsequent methodological specifications, strategies, and interventions that lead to further reductions in medicine prices in many countries [16, 32, 43]. In addition, market completion can further decrease medicine prices. In Saudi Arabia, in the public healthcare sector, further reductions in medicine prices are achieved via unified procurement and the competitive tendering system. These large, centralized tenders utilize the power of group purchasing and help to provide further cost savings [1, 44]. However, the retail pharmacy prices of medicines, i.e. the prices set for the consumers at community pharmacies, are fixed, and they are printed on product packages. In addition, no discounts can be provided to medicine consumers by community pharmacies since this is legally not permitted in Saudi Arabia. Hence, to promote generic medicines, especially low-priced generic medicines, demand-side policies particularly educational activities and campaigns are needed to promote the cost-effective use of medicines. This needs to target both healthcare professionals and medicine consumers. This is particularly important since there is a general preference towards original brand medicines in Saudi Arabia [5] with negative perceptions towards generic medicines [45–48]. Moreover, only 47.9% of physicians surveyed by Salhia et al. (2015) indicated that they are familiar with the price differences [46]. In addition, this is not helped by the current myths regarding generic medicines, i.e. the association between low price and low quality and effectiveness, as reported in the literature [49–52]. Hence, educational campaigns need to highlight the facts regarding generic medicines, which are clinically interchangeable with the original brand medicines, with the same quality, safety, and effectiveness, (the only difference is their cheaper prices). In addition, the current rigorous registration system of medicines and post-marketing surveillance should be discussed in the campaigns to ensure awareness regarding this topic [1]. Additionally, incorporation of medicine prices in electronic prescribing systems, especially at private sectors, could help promote physician awareness regarding medicine prices and it could encourage cost-effective prescribing [53].
Strengths and limitations
The current study summarizes the key aspects of pharmaceutical pricing policy in Saudi Arabia, and it provides an analysis of the impact of this policy on medicine prices by studying the highest selling products in Saudi Arabia. However, this study has some limitations. The study analysed the prices of only six medicines, which is considered a small number; although, these are the top selling products. In addition, only one dosage form of these products was analysed. However, this is justified since the pricing policy takes into consideration the size and the type of dosage form when determining the price. However, we believe that the current study provides preliminary evidence that will be useful to health policymakers and researchers. Large comprehensive studies in this area are needed to further analyse the aspects of this policy for future improvement and revisions.
Conclusion
Medicine prices are strictly controlled through the pharmaceutical pricing policy in Saudi Arabia. Moreover, the current policy resulted in large price differences among medicines, including medicines of the same molecule. Due to this large difference, the cost savings will depend on the product that is prescribed or procured by the health organization.
Funding sources
None.
Competing interests: None.
Provenance and peer review: Not commissioned; externally peer reviewed.
References 1. Alrasheedy AA, Hassali MA, Wong ZY, Aljadhey H, AL-Tamimi SK, Saleem F. Pharmaceutical policy in Saudi Arabia. In: Babar ZUD, editor. Pharmaceutical Policy in Countries with Developing Healthcare Systems: Springer; 2017. p. 329-47. 2. Al Asmri M, Almalki MJ, Fitzgerald G, Clark M. The public healthcare system and primary care services in Saudi Arabia: a system in transition. East Mediterr Health J. 2019;25. doi.org/10.26719/emhj.19.049 3. Almalki M, Fitzgerald G, Clark M. Health care system in Saudi Arabia: an overview. East Mediterr Health J. 2011;17(10):784-93. 4. Business Monitor International. Saudi Arabia Pharmaceuticals & Healthcare Report Q3 2015. 5. Fitch Solutions Group. Saudi Arabia Pharmaceuticals & Healthcare Report Q3 2019. 6. World Health Organization. WHO guideline on country pharmaceutical pricing policies. 2015 [homepage on the Internet]. [cited 2020 Jan 23]. Available from: https://apps.who.int/iris/bitstream/handle/10665/153920/9789241549035_eng.pdf 7. Belloni A, Morgan D, Paris V. Pharmaceutical expenditure and policies. 2016 [homepage on the Internet]. [cited 2020 Jan 23]. Available from: https://www.oecd-ilibrary.org/social-issues-migration-health/pharmaceutical-expenditure-and-policies_5jm0q1f4cdq7-en 8. OECD. Pharmaceutical Expenditure. In: Health at a Glance 2017: OECD Indicators. London: OECD Publishing; 2017. 9. Hassali MA, Alrasheedy AA, McLachlan A, Nguyen TA, Al-Tamimi SK, Ibrahim MIM, et al. The experiences of implementing generic medicine policy in eight countries: a review and recommendations for a successful promotion of generic medicine use. Saudi Pharm J. 2014;22(6):491-503. 10. Hassali MA, Wong ZY, Alrasheedy AA, Saleem F, Yahaya AHM, Aljadhey H. Perspectives of physicians practicing in low and middle income countries towards generic medicines: a narrative review. Health Policy. 2014;117(3):297-310. 11. Verghese NR, Barrenetxea J, Bhargava Y, Agrawal S, Finkelstein EA. Government pharmaceutical pricing strategies in the Asia-Pacific region: an overview. Mark Access Health Policy. 2019;7(1):1601060. 12. Yoo K-B, Lee SG, Park S, Kim TH, Ahn J, Cho M-H, et al. Effects of drug price reduction and prescribing restrictions on expenditures and utilisation of antihypertensive drugs in Korea. BMJ Open. 2015;5(7):e006940. 13. Mousnad MA, Palaian S, Shafie AA, Ibrahim MIM. Medicine expenditure and trends in National Health Insurance Funds Sudan. J Pharmacy Pract Comm Med. 2018;4(3). 14. Godman B, Shrank W, Andersen M, Berg C, Bishop I, Burkhardt T, et al. Policies to enhance prescribing efficiency in Europe: findings and future implications. Front Pharmacol. 2011;1:141. 15. Godman B, Wettermark B, Van Woerkom M, Fraeyman J, Alvarez-Madrazo S, Berg C, et al. Multiple policies to enhance prescribing efficiency for established medicines in Europe with a particular focus on demand-side measures: findings and future implications. Front Pharmacol. 2014;5:106. 16. Vitry AI, Thai L, Roughead EE. Pharmaceutical pricing policies in Australia. In: Babar ZUD, editor. Pharmaceutical prices in the 21st century: Springer; 2015. p. 1-23. 17. Kwon H-Y, Yang B, Godman B. Key components of increased drug expenditure in South Korea: implications for the future. Value Health Reg Issues. 2015;6:14-21. 18. Pataky R, Tran DA, Coronado A, Alvi R, Boehm D, Regier DA, et al. Cancer drug expenditure in British Columbia and Saskatchewan: a trend analysis. CMAJ Open. 2018;6(3):E292-E9. 19. Schumock GT, Stubbings J, Wiest MD, Li EC, Suda KJ, Matusiak LM, et al. National trends in prescription drug expenditures and projections for 2018. Am J Health Syst Pharm. 2018;75(14):1023-38. 20. Prada SI, Soto VE, Andia TS, Vaca CP, Morales ÁA, Márquez SR, et al. Higher pharmaceutical public expenditure after direct price control: improved access or induced demand? The Colombian case. Cost Eff Resour Alloc. 2018;16(1):8. 21. Xiong Y, Cui Y, Zhang X. Pharmaceutical expenditure and total health-care expenditure in OECD countries and China: bidirectional Granger causality on the basis of health level. Expert Rev Pharmacoecon Outcomes Res. 2019:1-8. 22. Dylst P, Simoens S. Generic medicine pricing policies in Europe: current status and impact. Pharmaceuticals. 2010;3(3):471-81. 23. Zeng W. A price and use comparison of generic versus originator cardiovascular medicines: a hospital study in Chongqing, China. BMC Health Serv Res. 2013;13(1):390. 24. Godman B, Abuelkhair M, Vitry A, Abdu S, Bennie M, Bishop I. Payers endorse generics to enhance prescribing efficiency: impact and future implications, a case history approach. Generics and Biosimilars Initiative Journal. 2012;1(2):69-83. doi:10.5639/gabij.2012.0102.017 25. Lucchesi S, Marcianò I, Panagia P, Intelisano R, Randazzo MP, Sgroi C, et al. Prevalence of use and cost of biological drugs for cancer treatment: a 5-year picture from Southern Italy. Clin Drug Investig. 2018;38(3):269-78. 26. Selden TM, Abdus S, Miller GE. Decomposing changes in the growth of U.S. prescription drug use and expenditures, 1999-2016. Health Serv Res. 2019;54(4):752-63. 27. Roughead EE, Kim D-S, Ong B, Kemp-Casey A. Pricing policies for generic medicines in Australia, New Zealand, the Republic of Korea and Singapore: patent expiry and influence on atorvastatin price. WHO South East Asia J Public Health. 2018;7(2):99. 28. Godman B, Hill A, Simoens S, Kurdi A, Gulbinovič J, Martin A, et al. Pricing of oral generic cancer medicines in 25 European countries; findings and implications. Generics and Biosimilars Initiative Journal. 2019;8(2):49-70. doi:10.5639/gabij.2019.0802.007 29. Godman B, Shrank W, Wettermark B, Andersen M, Bishop I, Burkhardt T, et al. Use of generics—a critical cost containment measure for all healthcare professionals in Europe? Pharmaceuticals. 2010;3(8):2470-94. 30. Simoens S. A review of generic medicine pricing in Europe. Generics and Biosimilars Initiative Journal (GaBI Journal). 2012;1(1):8-12. doi:10.5639/gabij.2012.0101.004 31. Moodley R, Suleman F. The impact of the single exit price policy on a basket of generic medicines in South Africa, using a time series analysis from 1999 to 2014. PloS One. 2019;14(7):e0219690. 32. Vogler S, Martikainen JE. Pharmaceutical pricing in Europe. In: Babar ZUD, editor. Pharmaceutical prices in the 21st century: Springer; 2015. p. 343-70. 33. Dunlop WC, Staufer A, Levy P, Edwards GJ. Innovative pharmaceutical pricing agreements in five European markets: a survey of stakeholder attitudes and experience. Health Policy. 2018;122(5):528-32. 34. Ministry of Health of Saudi Arabia. [Executive regulations of the pharmaceutical institutions and products law 2005]. Arabic. [homepage on the Internet]. [cited 2020 Jan 23 ]. Available from: https://www.moh.gov.sa/en/Ministry/Rules/Documents/Regulation-of-Pharmaceutical-Products-and-Institutions.pdf 35. Ministry of Health of Saudi Arabia. [Pharmaceutical institutions and products law 2004]. Arabic. [homepage on the Internet]. [cited 2020 Jan 23 ]. Available from: https://www.moh.gov.sa/Ministry/Rules/Documents/008.pdf 36. Saudi Food and Drug Authority (SFDA). [The rules of pricing of medicines 2011]. Arabic. [homepage on the Internet]. [cited 2020 Jan 23 ]. Available from: https://www.sfda.gov.sa/ar/drug/drug_reg/Pages/drug_reg.aspx 37. AlKhamees OA, AlNemer KA, Maneea MWB, AlSugair FA, AlEnizi BH, Alharf AA. Top 10 most used drugs in the Kingdom of Saudi Arabia 2010–2015. Saudi Pharm J. 2018;26(2):211-6. 38. Shafie AA, Hassali MA. Price comparison between innovator and generic medicines sold by community pharmacies in the State of Penang, Malaysia. Journal of Generic Medicines. 2008;6(1):35-42. 39. Saudi Food and Drug Authority (SFDA). Official List of registered drugs and herbal products-2019 [homepage on the Internet]. [cited 2020 Jan 23]. Available from: https://www.sfda.gov.sa/en/drug/search/Pages/default.aspx. 40. Kwon H-Y, Godman B. Drug pricing in South Korea. Appl Health Econ Health Policy. 2017;15(4):447-53. doi:10.1007/s40258-017-0307-0 41. Wanis H. Pharmaceutical pricing in Egypt. In: Babar ZUD, editor. Pharmaceutical Prices in the 21st Century: Springer; 2015. p. 59-78. 42. Sermet C, Andrieu V, Godman B, Van Ganse E, Haycox A, Reynier J-P. Ongoing pharmaceutical reforms in France. Appl Health Econ Health Policy. 2010;8(1):7-24. 43. Håkonsen H, Sundell KA. Pharmaceutical pricing policies in Norway and Sweden. In: Babar ZUD, editor. Pharmaceutical Prices in the 21st Century: Springer; 2015. p. 209-27. 44. World Health Organization. Saudi Arabia pharmaceutical country profile 2012 [homepage on the Internet]. [cited 2020 Jan 23 ]. Available from: http://www.who.int/medicines/areas/coordination/Saudi_ArabiaPSCP_Narrative2012-04-18_Final.pdf 45. Albarraq AA. Consumers’ perceptions on generic medicines in Taif city, Saudi Arabia. Saudi Journal for Health Sciences. 2013;2(1):18-22. 46. Salhia HO, Ali A, Rezk NL, El Metwally A. Perception and attitude of physicians toward local generic medicines in Saudi Arabia: a questionnaire-based study. Saudi Pharm J. 2015;23(4):397-404. 47. Albadr Y, Khan TM. Factors influencing community pharmacist decision to dispense generic or branded medicines; Eastern Province, Alahsa, Saudi Arabia. Saudi Pharm J. 2015;23(2):143-6. 48. Alkhuzaee FS, Almalki HM, Attar AY, Althubiani SI, Almuallim WA, Cheema E, et al. Evaluating community pharmacists’ perspectives and practices concerning generic medicines substitution in Saudi Arabia: a cross-sectional study. Health Policy. 2016;120(12):1412-9. 49. Kaplan WA, Ritz LS, Vitello M, Wirtz VJ. Policies to promote use of generic medicines in low and middle income countries: a review of published literature, 2000–2010. Health Policy. 2012;106(3):211-24. 50. Theodorou M, Tsiantou V, Pavlakis A, Maniadakis N, Fragoulakis V, Pavi E, et al. Factors influencing prescribing behaviour of physicians in Greece and Cyprus: results from a questionnaire based survey. BMC Health Serv Res. 2009;9(1):150. 51. Jamshed SQ, Hassali MAA, Ibrahim MIM, Babar ZUD. Knowledge attitude and perception of dispensing doctors regarding generic medicines in Karachi, Pakistan: a qualitative study. J Pak Med Assoc. 2011;61(1):80-3. 52. Jamshed SQ, Ibrahim MIM, Hassali MAA, Masood I, Low BY, Shafie AA, et al. Perception and attitude of general practitioners regarding generic medicines in Karachi, Pakistan: a questionnaire based study. Southern Med Rev. 2012;5(1):22-30. 53. Wong ZY, Hassali MA, Alrasheedy AA, Saleem F, Yahaya AHM, Aljadhey H, et al. Medical specialists’ knowledge, perceptions and views about generic medicines in Malaysia: findings from a qualitative study and the implications. J Generic Med. 2015;12(2):60-73.
Author: Alian A Alrasheedy, BPharm(Hons), MPharm(Clin), PhD, MACP, RPh, Dean, Unaizah College of Pharmacy, Qassim University, Saudi Arabia
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Introduction and study objectives: Benefit-risk evaluations are essential throughout the life cycle of a drug to guarantee therapeutic efficacy for the authorized indications without an unacceptable incidence of adverse effects. To achieve this, a registry, assessment of adverse drug reactions (ADRs) and other pharmacovigilance (PhV) procedures are mandatory. Due to the inherent variability of bioproduction, this is particularly important for biological medicines, including biosimilars. Bevax®, a biosimilar of the reference product bevacizumab (Avastin®), first launched in Argentina in November 2016 after authorization was granted in June 2016. Since launch, an active PhV programme has registered and assessed the incidence of ADRs related to the post-marketing use of Bevax®. The aim of this descriptive study was to analyse and summarize the data contained in the treatment registry (TR) surveillance database established to monitor the post-marketing use of Bevax®. Methods: Data (including indications and associated ADRs) related to patients treated with Bevax® recorded in the Argentinian TR database from November 2016 to 28 May 2018 was analysed. Results: 818 registry forms were collected during the study interval, from which follow-up was available for 416. The product was used for approved indications in most patients (N = 805, 98.4%). A total of 44 individual case safety reports (ICSRs) were received involving 51 ADRs (26 serious). The most frequently reported ADR was related to underlying disease progression (15 events), followed by off-label use (11 events) and hypertension (5 events). Other ADRs with more than one report were neutropenia, sepsis and epistaxis (two events each), whilst the remaining ADRs were reported as single events. Discussion: Data from the Argentinian TR supports the clinical use of Bevax® for the authorized indications, with any associated ADRs generally being consistent with those of the reference product. There was no evidence of specific patterns and reports were generally in accordance with the known safety profile of bevacizumab. Nevertheless, the relatively low number of ICSRs precludes the establishment of a reliable safety profile for the product in this context. Conclusion: This may be the first published report summarizing the post-marketing pattern of use and ADRs associated with a biosimilar in Latin America. It emphasizes the need to further develop and implement additional effective PhV activities to increase knowledge of biosimilar safety and to promote the rational use of these products.
Submitted: 13 June 2018; Revised: 17 October 2018; Accepted: 17 October 2018; Published online first: 30 October 2018
Introduction and study objectives
A place for biosimilars During recent years, biological products have been established as an effective and essential therapeutic approach to treat a host of potentially life-threatening conditions, including cancer [1]. A biological medicine is a substance derived from a living organism used for the prevention or treatment of disease. These include monoclonal antibodies, cell therapies, cytokines and growth factors [2, 3]. At the molecular level, they are typically large recombinant proteins with complex post-translational modifications. Unlike small molecule drugs, which can be chemically synthesized, biological drugs are produced by genetic recombination techniques in living cells, requiring advanced and complex manufacturing and production processes [2, 4]. In spite of their clear utility as therapeutic agents, these products have a high per-unit acquisition cost due to elevated development and production costs [2]. Lack of access to expensive medications is a significant threat to global health care, involving complex sociopolitical factors. The problem is even more significant in low- and middle-income countries, such as those in Latin America [5]. The World Health Assembly in 2014 adopted a resolution recognizing the importance of increasing access to biotherapeutic products, by improving their affordability while assuring their quality, safety and efficacy [6]. Therefore, strategies to reduce cost and increase availability of such products are desirable. One such strategy is biosimilar development. A biosimilar refers to a biological product (a medicine that contains one or more active substances made by or derived from a biological source) that is similar (but not identical) to a previously authorized biological medicine (referred to as the originator or reference product) whose patent protection has expired [2, 4, 7–10]. The main rationale for the introduction of biosimilars is economic [4]. As occurs with generic drugs, their introduction into the market is likely to reduce costs substantially, thereby improving the availability of treatment for patients [1, 2, 4, 10].
Unlike small molecule drug products, biological therapies based on structurally complex, high molecular weight molecules cannot be reproduced in an identical form [11]. Due to such structural complexity and the inherent variability of biological expression systems, biological drugs including biosimilars, are expected to exhibit a certain degree of variability (microheterogeneity), even between different batches of the same product [9]. This variability affects the precise nature of the end product, which can potentially alter both the clinical efficacy and safety profile of the product [3, 4, 12]. A biosimilar should not exhibit significant variability compared to the reference product and all critical quality attributes, i.e. those important for the function of the molecule, must be comparable [13, 14]. However, a thorough comparison of structural and functional characteristics, product and process-related impurities of the biosimilar and the reference product is necessary, with any identified differences explained and the potential impact on the clinical performance of the biosimilar discussed [9, 12, 15–17]. To permit the use of a biosimilar and reference product for the same indications there should be no clinically meaningful differences in terms of efficacy and safety [18].
Regulatory perspective for biosimilars: post-authorization surveillance issues The European Medicines Agency (EMA) has pioneered the regulatory framework for biosimilars and approved a total of 37 biosimilars (23 different applications) for 12 active substances since 2005 [19]. Regulatory authorities including EMA, US Food and Drug Administration (FDA) and World Health Organization (WHO) have adopted unique but similar measures for biosimilars, recognizing that the approval process for generic medicines cannot be applied to biosimilars [16]. Guidance from these organizations has been adopted as a reference for countries worldwide [8]. The consensus of the regulatory agencies is that the approval of biosimilars should be based on determination of similarity with the reference product, using evidence from comprehensive comparability studies and robust pharmaceutical quality data. By demonstrating high similarity with the reference medicine, the biosimilar can largely rely on the efficacy and safety data obtained with the reference product [4, 20].
However, since data from pre-authorization clinical studies may be insufficient to identify all potential differences between biological products, post-authorization monitoring is an essential requirement for refining the efficacy and safety profile of biosimilars [4, 20, 21]. As for all therapeutic agents, this monitoring is carried out through pharmacovigilance (PhV) practice, defined by WHO as ‘the science and activities relating to the detection, assessment, understanding and prevention of adverse effects or any other drug-related problems’ [22]. PhV therefore emerges as a crucial tool in the identification and prevention of adverse drug reactions (ADRs), thus promoting patient safety and the rational use of medicines [21]. Although there are currently no specific safety requirements for biosimilars, it is widely recognized that PhV activities are of paramount importance for biological medicines due to the variability inherent to bioproduction [23, 24]. As a result, pharmaceutical companies are encouraged to implement an active PhV programme once a biosimilar is marketed, in which the need to ensure continuous product and batch traceability in clinical use is a key requirement [4, 8, 20, 21, 23–26]. Proposed surveillance strategies are varied but comprise several activities that exceed passive vigilance in order to collect real-world data. These active surveillance strategies might include surveillance of electronic healthcare databases, observational studies, targeted clinical investigations and treatment registries (TRs) [11, 27]. In addition, biosimilars are encouraged to participate in already established pharmacoepidemiological studies for the reference product with the aim to collect safety information on the molecule and not to compare the safety profile of the biosimilar and reference product per se as the biosimilarity exercise has shown that the biosimilar is similar to the reference product [13].
Focusing on a bevacizumab biosimilar (Bevax®) Biosimilars, in particular monoclonal antibodies, have been established as an essential component of the oncology treatment arsenal [1]. Among them, bevacizumab, a humanized monoclonal antibody against vascular endothelial growth factor (VEGF), is an important therapeutic option for a variety of cancer types, with a generally good safety profile [28–31]. Bevacizumab exerts its antineoplastic effects by inhibiting the activity of VEGF, the key driver of vasculogenesis and angiogenesis, resulting in regression of the tumour vasculature [29, 32]. The original bevacizumab (Avastin®, marketed by Roche) was approved in 2004 in the US and in 2005 in Europe as a first-line treatment for metastatic colorectal cancer in combination with chemotherapy [32]. It has since been approved for the treatment of other cancers, in combination with other chemotherapy agents [28, 29, 31–33]. The most common side effects of Avastin® are hypertension, tiredness or asthenia (physical weakness), diarrhoea and abdominal pain, although more serious side effects, including gastrointestinal perforation, haemorrhage (bleeding) and arterial thromboembolism, have been reported [30]. A comprehensive list of ADRs related to bevacizumab and to Avastin® is available elsewhere [28, 34].
Bevax®, developed and supplied by Spanish-based mAbxience, is a biosimilar of Avastin® (bevacizumab). In Argentina, Bevax® was authorized in June 2016 [35] and commercialized from November 2016 by Laboratorios Elea Phoenix. Similar to its reference product, Bevax® is authorized in Argentina for the treatment of forms of cancer in combination with chemotherapy, including metastatic colorectal cancer, epithelial ovarian cancer, recurrent metastatic or persistent cervical cancer, metastatic breast cancer, advanced non-small cell lung cancer, glioblastoma, and advanced or metastatic renal cell carcinoma [35]. Currently, Bevax® is also commercialized in Ecuador and Paraguay. The safety profile of Bevax® is expected to be the same as its reference product, Avastin® [34]. Despite being structurally very similar, there has been continuous debate regarding whether biosimilars have different benefit-risk profiles to the reference product, as their approval is based only on a comparability exercise and not an assessment of their benefit-risk profile [9, 10, 12, 18]. Since its launch, Bevax® has been subject to an active PhV programme as part of the risk management plan (RMP), created to establish its safety profile by assessing the incidence of ADRs related to its use. In line with European guidelines [13, 26, 36], PhV events are recorded by brand name, active pharmaceutical ingredient (API) and batch information to guarantee traceability. As an initial stage in this programme, a Treatment Registry (TR) was established in order to collect data from patients treated with Bevax®. This is useful to understand the clinical use of Bevax®, determine its safety profile and to support further safety assessment steps, which may include protocolized post-authorization safety studies (PASS).
The aim of this study was to describe and summarize data retrieved from the TR surveillance database on the biosimilar Bevax® established as part of the PhV programme for the product. Data were collected in Argentina between November 2016 and May 2018.
Methods
The data presented here were collected from the TR database implemented for Bevax® since its commercialization in November 2016. The TR was conducted in accordance with the RMP approved by Argentinian National Administration of Drugs, Foods and Medical Devices (ANMAT) in accomplishment of good pharmacovigilance practices (GVPs). The analysed patient dataset was anonymized using an Identification Code not related with patient personal data, following the applicable normative for personal data protection. The data lock point (DLP; the cut-off date for data inclusion in the study) for this report was 28 May 2018.
To establish the data registry, healthcare professionals (HCPs) treating patients with Bevax® were asked to complete three forms for each patient. First, an initial ‘Notification form’ in which information related to the patient (e.g. patient’s name, initials, sex, age, weight), performance status, clinical indication and treatment details (e.g. dose, frequency, date of first infusion) was registered. Approximately five months after starting treatment, an ‘Outcome form’ was sent to HCPs requesting information regarding treatment evolution in patients treated with Bevax®, including any ADR or case of death. If any product-associated ADR or death occurred, HCPs were asked to complete an ‘ICSR (Individual Case Safety Report) form’, with the intention of gathering detailed information on the suspected ADR, including suspected drug reactions and medical history, in a similar format to standardized registry forms available elsewhere [37].
All detected ADRs were coded using preferred terms from the Medical Dictionary for Regulatory Activities (MedDRA, version 21.0) and grouped using the System Organ Classes (SOCs) classifications of MedDRA. Furthermore, ADRs were classified as either ‘serious’ or ‘non-serious’. In general, a serious ADR would refer to any untoward medical occurrence that 1) results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization; 2) results in persistent or significant disability/incapacity; or 3) results in a congenital anomaly/birth defect or any other important medical event [38].
All data received in the TR database concerning Bevax® were extracted and analysed using appropriate descriptive statistics for either categorical or continuous variables.
Results
A total of 818 notification forms were registered in the TR database for patients who began treatment with Bevax® during the study period. Among these forms, follow-up information was available for 416 patients. The distribution of treatment duration for these patients was highly symmetrical as illustrated in Figure 1, showing a median (interquartile range) of 220 days (175 to 275 days). A total of 44 ICSRs describing ADRs associated with the product were received during the study period, amounting to 9.3% (95%CI: 6.7-11.9) of the total notification forms registered in the TR.
However, it should be noted that all safety information during the period covered by this study came from the TR and no additional ICSRs were independently reported.
Demographic data for the whole study population, as detailed on the notification forms for Bevax® retrieved in the TR and data regarding clinical indications for which the product was used, are summarized in Table 1. Most patients were women (51.8%), with a mean age of 60.5 years (ranging from 6 to 87 years). Men accounted for 41% with a mean age of 64.9 years (ranging from 9 to 88 years). The sex for six of the patients (0.7%) remained unknown since it was not recorded on the notification form. The mean age of the whole study population was of 64.5 years, with a range of 6 to 88 years.
In general, most patients (98.4%) received Bevax® for treating the types of cancer included in the authorized indications. Metastatic colorectal cancer was by far the most commonly treated indication (59.0%), followed by epithelial ovarian cancer (17.7%). As expected, breast and gynaecologic (cervical and ovarian) cancers were treated exclusively in women. However, for the remainder of the indications, men appeared to be treated more frequently with Bevax®, see Table 1. Additionally, for a small number of patients (1.3%) the product was used for treating a variety of other cancer types for which it is not currently authorized (unlabelled indications), although no specific patterns were detected. The use of the product for unlabelled indications was considered an ADR (off-label use) due to the potential for undetermined risks. Among them, there were four cases in which Bevax® was used in patients under the age of 18. As stated in the summary of product characteristics (SmPC) for Avastin® [34], since safety and efficacy has not been established in children under 18 years old, bevacizumab is only indicated in the adult population. Therefore, use in this population is considered off-label. However, no ADRs were reported in the four underage patients.
As described above, a total of 44 ICSRs (23 serious) were received during the study period. These ICSRs were associated with a total of 51 ADRs, 26 of which were considered serious events, see Table 2. The most frequently reported ADRs were related to a deterioration of the underlying disease (disease progression) and to the use of the product for an unauthorized indication (off-label use) with 15 and 11 occurrences, respectively. Hypertension was the next most reported ADR, with five occurrences. The remaining ADRs appeared mostly as single occurrences without any specific reporting pattern. The most commonly identified SOCs were related to general disorders and administration site conditions (including the ADR of disease progression) as well as injury, poisoning and procedural complications (including the ADR for off-label use). SOCs for vascular disorders (including events of hypertension) and skin and subcutaneous tissue disorders, were also identified, although with much lower frequencies. Of interest, and as detailed in Table 3, ADRs associated with Bevax® are in line with those expected with bevacizumab and are generally in accordance with those associated with the reference product Avastin®.
Twenty-three of the 44 ICSRs were related to serious ADRs and were therefore classified as serious cases. Death was reported in 20 of these serious cases, the majority (15 of the 20; 75%) resulting from disease progression. As further detailed in Table 4, four of the patients died during treatment: two of them as a result of developing sepsis, one due to a subarachnoid haemorrhage after severe thrombocytopenia and the remaining patient, with a previous history of cardiovascular disease, suffered sudden death. A fifth patient died from a stroke 44 days after taking the last dose of Bevax®. Lack of detailed additional information for these cases precluded more precise analysis. Sepsis, thrombocytopenia and cerebrovascular accidents associated with arterial thromboembolism are all serious ADRs known to be associated with the use of bevacizumab and are listed with a frequency ranging from common to very common [34]. Additionally, it should also be noted that the majority of these patients (4 out of 5) were over 65 years of age, see Table 4, a population in which the use of bevacizumab is associated with a higher frequency of thrombocytopenia and an increased risk of developing arterial thromboembolic reactions, including cerebrovascular accidents, transient ischaemic attacks and myocardial infarctions [34].
Discussion
Biosimilar medicines have emerged as a valuable and affordable therapeutic option for treating a variety of conditions, including cancer. However, the complex nature of these products and the variability inherent to any biological expression system has generated a need for a robust regulatory environment and the implementation of active post-marketing PhV programmes, intended to gather data around the use of the biosimilar in clinical practice [4, 8, 20, 24, 25]. All biological products, including biosimilars, are subjected to a rigourous PhV programme within a RMP to continuously monitor for and appropriately manage the risks associated with their use [8, 24]. RMPs for biological products should focus on strengthening the PhV measures and implementing effective post-marketing surveillance to identify any ADRs, but particularly to identify immunogenicity risks associated with the variability inherent to biological products [21, 39]. Considering the known limitations of randomized clinical trials as well as those inherent to the abbreviated dossier submitted as part of the marketing application for biosimilars, post-marketing safety data, as that contained in TRs, appears as a valuable and necessary complement. In this context, PhV emerges as an important tool to obtain additional data for evaluating the safety of biosimilars. There is consensus among the major regulatory agencies that similarity to the reference product in terms of robust and comparable pharmaceutical quality is a mandatory requirement for the approval of a biosimilar [13, 15, 16]. Despite such consensus, there are numerous differences in the manner that regulatory authorities regulate the entrance of biosimilars into their markets. In Latin America, the subject of this study, regulatory authorities have begun to establish well described and standardized pathways that permit a biosimilar to gain commercial licensure. Although robust biosimilar legislation has been implemented in many Latin American countries, there remains a need to improve PhV systems in some of these countries and to encourage recognition of the value of PhV and related procedures [40, 41].
As a bevacizumab biosimilar, the safety profile of Bevax® is expected to be the same as its reference product Avastin®. However, as a biological product and due to the variability inherent to bioproduction, some minor potential differences may exist between Bevax® and Avastin® that could have clinical and safety implications. Therefore, post-authorization studies evaluating the safety profile of bevacizumab and derived biosimilar products are of paramount importance. In this context, the present study intended to summarize and analyse the data retrieved from a TR data surveillance database established as part of the pharmacovigilance programme for Bevax®. To this purpose, safety data from the post-marketing use of the product contained in the TR received in Argentina during the period from November 2016 (when Bevax® was first commercialized) up to 28 May 2018 were retrieved, summarized and is herein presented.
Literature on post-marketing surveillance studies with biosimilars is scarce and, this may be the first published study to summarize the pattern of use and ADRs associated with a biosimilar from post-marketing, clinical experience in Latin America. The study analysed a total of 818 notification forms. Despite limitations due to the low number of ICSRs, the data presented here suggests Bevax® possesses a post-marketing safety and tolerability profile comparable to its reference product, Avastin®. ADRs associated with Bevax® in the present study are generally in concordance with that of the reference product Avastin®, see Table 3, since practically all ADRs associated with Bevax® are also listed events in the SmPC of the originator product [34]. Hypertension (high blood pressure), asthenia (weakness), arthralgia (joint pain), pyrexia (fever), epistaxis (nasal haemorrhage), as well as neutropenia and thrombocytopenia (reduced platelet count) reported here mostly as single occurring events, are all common side effects of bevacizumab which are also listed for Avastin, see Table 2 for details.
Some of the ADRs registered by Bevax® (e.g. subarachnoid haemorrhage and related cerebrovascular accident) are similar to those expected for the reference bevacizumab such as haemorrhage (bleeding) and arterial thromboembolism (blood clots in the arteries). Interestingly, commonly occurring events related to the gastrointestinal system such as diarrhoea, nausea and abdominal pain or gastrointestinal perforation (usually classified as serious events to bevacizumab) were not recorded for Bevax®. Disregarding non-specific ADRs or those associated with the use of any drug (e.g. disease progression and off-label use) hypertension was the most frequently reported ADR. Although other ADRs were reported, these mostly occurred as single events without a specific reporting pattern. All hypertension events were reported as non-serious. Furthermore, hypertension is a recognized ADR of bevacizumab [28] and is described in the SmPC of both Bevax® [35] and the reference product Avastin® [34], with the advice to manage symptoms, where possible, with anti-hypertensives. Besides death due to disease progression, death occurred in five additional cases. However, this is in line with data previously published for the reference product [42, 43] and, although lack of additional information for most of these cases precluded further analysis, death could be explained by the listed ADRs of the product and is commonly associated with the use of bevacizumab, especially in aged patients [30].
Previous studies have evaluated the post-authorization safety profile of Avastin® in daily medical practice in Italian [43] and French populations [42], in which the frequency and severity of reported ADRs associated with bevacizumab were generally in agreement with that described in the SmPC of the reference product and therefore in accordance with data presented for Bevax® in the present study. The safety profile for Bevax® therefore appears to be not only consistent with that of the reference product Avastin®, but also with that from in vitro and in vivo preclinical studies and with the clinical efficacy and safety profile demonstrated in a comparative clinical trial (Data on file) [44]. This was an open-label, parallel-group randomized controlled trial (BEVZ92-A-01-13) to compare pharmacokinetics, efficacy, safety, and immunogenicity of the bevacizumab biosimilar BEVZ92 versus reference bevacizumab (Avastin) in combination with FOLFOX or FOLFIRI as first-line treatment in patients with metastatic colorectal cancer (NCT02069704). Overall, data regarding ADRs and therefore the safety profile of Bevax® is consistent with published data for the reference product and previously published data [30, 34]. Additionally, data available from the 818 individual notification forms for patients initiating treatment with Bevax® confirmed that most physicians prescribed the product for approved indications (98.4%), but in a small proportion of cases (1.3%) also for unauthorized indications, see Table 1. This is also in accordance with previous studies concerning the reference product Avastin®, which show use of bevacizumab for a variety of off-label conditions [42] but mostly for specified indications.
Despite the valuable data presented here, it is important to address the limitations of the present study. Methodological limitations must always be considered when collecting data on adverse effects, as the methods used for recording adverse events may influence the type and the frequency of effects reported. For example, patients may specify more adverse events when checking off a standardized list of symptoms than when reporting them spontaneously [45]. In this study however, the spontaneous nature of adverse event communication, the type of the ADRs reported and the physiopathological causes involved in most cases, suggest that a putative ‘nocebo’ effect has not significantly influenced the data recorded for Bevax® and considered in the present study. Although a substantial number of registry forms were collected in the TR, follow-up data were only available for approximately half of the forms. This was mostly due to a lack of follow-up caused by delays in receiving the outcome form and/or the ICSR from HCPs, resulting in a significant number of forms being received outside of the data lock point established for the study. Similarly, and as mentioned above, the number of ICSRs containing completed and detailed information was relatively low, accounting for less than 10% of the total notification forms received during the study period. Besides preventing a reliable assessment of the safety profile, this precluded a robust statistical analysis of confounders, which may have influenced estimates of ADR occurrences. Furthermore, additional factors, such as concomitant drug therapies, comorbidities, disease stage and disease-related risk, were not comprehensively considered. Since bevacizumab is used in addition to standard chemotherapy, e.g. capecitabine, paclitaxel, oxaliplatin, carboplatin, irinotecan, the effect of concomitant agents on the occurrence of ADRs cannot be excluded. Therefore, the present descriptive data regarding the safety profile of Bevax® must be considered purely exploratory since the small sample size and limited availability of detailed data restricted our ability to detect valuable trends. In the future, further comprehensive studies to evaluate the safety profile of Bevax®, and other biosimilar products, will be forthcoming. In particular, a post-authorization safety study (PASS) with a PhV collection data protocol is planned in Argentina for the near future.
Conclusion
To our knowledge, this is the first published report summarizing the pattern of use and ADRs associated with a biosimilar from post-marketing experience in Latin America. The Bevax® (bevacizumab) TR implemented as part of the RMP for the product in Argentina has proven to be a useful tool to enable reporting in oncological treatments involving this biosimilar product as reports coming from spontaneous sources are very limited in Argentina. Although a reliable safety profile of the product cannot be established here due to the limited number of ICSRs received during the study period, the ADRs associated with Bevax® are mostly in concordance with that of the reference product and consistent with previously published data.
The results of the TR support the implementation of additional actions to obtain further knowledge related to biosimilars, which is important to promote patient safety and improve the rational use of biosimilars. Further comprehensive safety studies to support benefit-risk evaluations for biosimilar products are currently being considered.
Regulatory basis for the approval of biosimilars in Argentina In Argentina, the regulatory body for approval of all medicines, including the scientific evaluation of biologicals and biosimilars is the Administración Nacional de Medicamentos, Alimentos y Tecnología Médica (National Administration of Drugs, Foods and Medical Devices; ANMAT; www.anmat.gov.ar), under the authority of the Ministry of Health. With the effort to harmonize regulatory requirements for Biological products, ANMAT published the first three guidelines (for both new and biosimilar molecules) throughout 2011–2012, in which the scientific principles for the evaluation and regulatory issues for the approval of biological products in Argentina were established. The specific guideline for the development of biosimilar products is established specifically through Disposition 7729/11 [46] approved on 14 November 2011. The main requirements in the guideline are as follows: 1. Reference product must be approved by ANMAT or any other regulatory agency (high regulatory/pharmacovigilance status, Australia, EU, Japan, USA) and be marketed in the same territories. Reference product must be approved with full dossier information. 2. Biosimilar applicant must provide API Information (aminoacid sequence, glycosylation site(s), post-translational modifications, secondary structure, tertiary structure, high-order structures, identification, biological activity (in the case of mAbs Fab/Fc functions), purity). 3. Biosimilar candidate must have the same pharmaceutical dosage form, route of administration, therapeutic indications. The manufacturing process used for the manufacture of the API and DP must be similar to those used for the reference product (cell line, upstream, downstream). 4. Applicant must perform an analytical comparability exercise to confirm the high similarity of the biosimilar candidate to the reference product. 5. The analytical comparability exercise must provide information about physicochemical characteristics, biological activity, mechanism of action, purity, glycosylation, postranslational modifications. 6. The need to perform preclinical and clinical studies will depend on the evidence obtained in the first stage of the analytical comparability exercise, and the type and nature of molecule to be evaluated. If clinical studies are requested, non-inferiority and equivalence studies are accepted. Efficacy endpoint should not be the primary endpoint of the study since efficacy has been already established by the reference product. If a PD marker is available, ANMAT [46] encourage its use in clinical studies. 7. Once the biosimilar is approved, the applicant must elaborate and apply a product-specific risk management plan.
Acknowledgements
The authors would like to thank all those researchers and healthcare professionals who participated in collection, recording and registry of the data used in this study and who proactively shared their experience of using our biosimilar product, as well as all the patients whose data were used in this study.
Funding
This study was supported by Laboratorio Elea Phoenix, SA and mAbxience Research SL.
Competing interests/Disclaimer: FF, MD, PRA and ES are employees of Laboratorio Elea Phoenix, the company that markets Bevax® in Argentina. NE is employed at mAbxience Research, the company that developed Bevax®. No disclaimer would affect Alvaro Romera.
Provenance and peer review: Not commissioned; externally peer reviewed.
1Laboratorio Elea Phoenix, Gral. Juan Gregorio Lemos 2809 (B1613 AUE), Los Polvorines, Buenos Aires, Argentina 2Clinical Oncologist, Principal Investigator of Rosario Oncologic Institute, Córdoba 2457, Rosario – Santa Fe, Argentina 3mAbxience Research SL, 4/F, 28 Manuel Pombo Angulo, ES-28050, Madrid, Spain
References 1. Nabhan C, Parsad S, Mato AR, Feinberg BA. Biosimilars in oncology in the United States: a review. JAMA Oncol. 2018;4(2):241-7. 2. Schiestl M, Zabransky M, Sörgel F. Ten years of biosimilars in Europe: development and evolution of the regulatory pathways. Drug Des Devel Ther. 2017;11:1509-15. 3. Chirino AJ, Mire-Sluis A. Characterizing biological products and assessing comparability following manufacturing changes. Nat Biotechnol. 2004;22(11):1383-91. 4. Emmanouilides CE, Karampola MI, Beredima M. Biosimilars: hope and concern. J Oncol Pharm Pract. 2016;22(4):618-24. 5. Ruiz R, Strasser-Weippl K, Touya D, Herrero Vincent C, Hernandez-Blanquisett A, St Louis J, et al. Improving access to high-cost cancer drugs in Latin America: much to be done. Cancer. 2017;123(8):1313-23. 6. World Health Organization. Access to biotherapeutic products including similar biotherapeutics products and ensuring their quality, safety and efficacy. WHA67.21. 24 May 2014 [homepage on the Internet] [cited 2018 Oct 17]. Available from: http://apps.who.int/gb/ebwha/pdf_files/WHA67/A67_R21-en.pdf 7. Declerck PJ. Biologicals and biosimilars: a review of the science and its implications. Generics and Biosimilars Initiative Journal (GaBI Journal). 2012;1(1):13-6. doi:10.5639/gabij.2012.0101.005 8. Khraishi M, Stead D, Lukas M, Scotte F, Schmid H. Biosimilars: a multidisciplinary perspective. Clin Ther. 2016;38(5):1238-49. 9. Weise M, Bielsky MC, De Smet K, Ehmann F, Ekman N, Giezen TJ, et al. Biosimilars: what clinicians should know. Blood. 2012;120(26):5111-7. 10. Kang HN, Knezevic I. Regulatory evaluation of biosimilars throughout their product life-cycle. Bull World Health Organ. 2018;96(4):281-5. 11. Inotai A, Csanadi M, Petrova G, Dimitrova M, Bochenek T, Tesar T, et al. Patient access, unmet medical need, expected benefits, and concerns related to the utilisation of biosimilars in Eastern European countries: a survey of experts. BioMed Res Int. 2018;2018:9597362. 12. Weise M, Kurki P, Wolff-Holz E, Bielsky MC, Schneider CK. Biosimilars: the science of extrapolation. Blood. 2014;124(22):3191-6. 13. European Medicines Agency. Guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: non-clinical and clinical issues. EMEA/CHMP/BMWP/42832/2005 Rev1. 2014 [homepage on the Internet]. [cited 2018 Oct 17]. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2015/01/WC500180219.pdf 14. U.S. Food Drug Administration. Scientific considerations in demonstrating biosimilarity to a reference product. 2015 [homepage on the Internet]. [cited 2018 Oct 17]. Available from: www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM291128.pdf 15. U.S. Food Drug Administration. Quality considerations in demonstrating biosimilarity of a therapeutic protein product to a reference product. 2015 [homepage on the Internet]. [cited 2018 Oct 17]. Available from: https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM291134.pdf 16. Knezevic I, Griffiths E. WHO standards for biotherapeutics, including biosimilars: an example of the evaluation of complex biological products. Ann N Y Acad Sci. 2017;1407(1):5-16. 17. Visser J, Feuerstein I, Stangler T, Schmiederer T, Fritsch C, Schiestl M. Physicochemical and functional comparability between the proposed biosimilar rituximab GP2013 and originator rituximab. BioDrugs. 2013;27(5):495-507. 18. Kurki P, van Aerts L, Wolff-Holz E, Giezen T, Skibeli V, Weise M. Interchangeability of biosimilars: a European perspective. BioDrugs. 2017;31(2):83-91. 19. Mielke J, Jilma B, Jones B, Koenig F. An update on the clinical evidence that supports biosimilar approvals in Europe. Br J Clin Pharmacol. 2018;84(7):1415-31. 20. Casadevall N, Edwards IR, Felix T, Graze PR, Litten JB, Strober BE, et al. Pharmacovigilance and biosimilars: considerations, needs and challenges. Expert Opin Biol Ther. 2013;13(7):1039-47. 21. Zuñiga L, Calvo B. Biosimilars: pharmacovigilance and risk management. Pharmacoepidemiol Drug Saf. 2010;19(7):661-9. 22. World Health Organization. The safety of medicines in public health programmes: pharmacovigilance an essential tool [homepage on the Internet]. [cited 2018 Oct 17]. Available from: http://www.who.int/medicines/areas/quality_safety/safety_efficacy/pharmvigi/en/ 23. Uhlig T, Goll GL. Reviewing the evidence for biosimilars: key insights, lessons learned and future horizons. Rheumatology (Oxford). 2017;56(suppl_4):iv49-iv62. 24. Calvo B, Zuniga L. EU’s new pharmacovigilance legislation: considerations for biosimilars. Drug Saf. 2014;37(1):9-18. 25. Declerck P, Farouk Rezk M. The road from development to approval: evaluating the body of evidence to confirm biosimilarity. Rheumatology (Oxford). 2017;56(suppl_4):iv4-iv13. 26. European Medicines Agency. Guideline on good pharmacovigilance practices (GVP). Product- or Population-Specific Considerations II: Biological medicinal products. EMA/168402/2014 Corr*. 2016 [homepage on the Internet]. [cited 2018 Oct 17]. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2016/08/WC500211728.pdf 27. Araújo FC, Sepriano A, Teixeira F, Jesus D, Rocha TM, Martins P, et al. The Portuguese Society of Rheumatology position paper on the use of biosimilars – 2017 update. Acta Reumatol Port. 2017;42(3):219-28. 28. Gerriets V, Kasi A. Bevacizumab. StatPearls[Internet]. Treasure Island (FL): StatPearls Publishing LLC; 2018. 29. Ferrara N, Hillan KJ, Novotny W. Bevacizumab (Avastin), a humanized anti-VEGF monoclonal antibody for cancer therapy. Biochem Biophys Res Commun. 2005;333(2):328-35. 30. European Medicines Agency. EPAR summary for the public: Avastin, bevacizumab. EMA/302947/2017, EMEA/H/C/000582 [homepage on the Internet]. [cited 2018 Oct 17]. Available from: https://www.ema.europa.eu/documents/overview/avastin-epar-summary-public_en.pdf 31. Drooger JC, van Tinteren H, de Groot SM, Ten Tije AJ, de Graaf H, Portielje JE, et al. A randomized phase 2 study exploring the role of bevacizumab and a chemotherapy-free approach in HER2-positive metastatic breast cancer: The HAT study (BOOG 2008-2003), a Dutch Breast Cancer Research Group trial. Cancer. 2016;122(19):2961-70. 32. Cheng YD, Yang H, Chen GQ, Zhang ZC. Molecularly targeted drugs for metastatic colorectal cancer. Drug Des Devel Ther. 2013;7:1315-22. 33. Trillsch F, Mahner S, Hilpert F, Davies L, García-Martínez E, Kristensen G, et al. Prognostic and predictive effects of primary versus secondary platinum resistance for bevacizumab treatment for platinum-resistant ovarian cancer in the AURELIA trial. Ann Oncol. 2016;27(9):1733-9. 34. European Medicines Agency. Avastin EPAR product information. Annex I: Summary of product Characteristics. 2017 [homepage on the Internet]. [cited 2018 Oct 17]. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000582/WC500029271.pdf 35. Administración Nacional de Medicamentos, Alimentos y Terapia Médica (ANMAT). Autorización Registro BEVAX. 2016 [homepage on the Internet]. [cited 2018 Oct 17]. Available from: http://www.anmat.gov.ar/boletin_anmat/junio_2016/Dispo_6069-16.pdf 36. European Medicines Agency. Guideline on similar biological medicinal products (CHMP/437/04 Rev 1). 2014 [homepage on the Internet]. [cited 2018 Oct 17]. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2014/10/WC500176768.pdf 37. Medicines and Healthcare products Regulatory Agency. Yellow Card. Yellow card for reporting suspected adverse drug reactions. 2017 [homepage on the Internet]. [cited 2018 Oct 17]. Available from: https://yellowcard.mhra.gov.uk/_assets/files/Healthcare-professional-Yellow-Card-form-February-2017.pdf 38. Edwards IR, Aronson JK. Adverse drug reactions: definitions, diagnosis, and management. Lancet. 2000;356(9237):1255-9. 39. Pineda C, Castañeda Hernandez G, Jacobs IA, Alvarez DF, Carini C. Assessing the immunogenicity of biopharmaceuticals. BioDrugs. 2016;30(3):195-206. 40. Azevedo VF, Mysler E, Álvarez AA, Hughes J, Flores-Murrieta FJ, Ruiz de Castilla EM. Recommendations for the regulation of biosimilars and their implementation in Latin America. Generics and Biosimilars Initiative Journal (GaBI Journal). 2014;3(3):143-8. doi:10.5639/gabij.2014.0303.032 41. Pineda C, Caballero-Uribe CV, de Oliveira MG, Lipszyc PS, Lopez JJ, Mataos Moreira MM, et al. Recommendations on how to ensure the safety and effectiveness of biosimilars in Latin America: a point of view. Clin Rheumatol. 2015;34(4):635-40. 42. Taugourdeau-Raymond S, Rouby F, Default A, Jean-Pastor MJ; French Network of Pharmacovigilance Centers. Bevacizumab-induced serious side-effects: a review of the French pharmacovigilance database. Eur J Clin Pharmacol. 2012;68(7):1103-7. 43. Scavone C, Sportiello L, Sullo MG, Ferrajolo C, Ruggiero R, Sessa M, et al. Safety profile of anticancer and immune-modulating biotech drugs used in a real world setting in Campania Region (Italy): BIO-Cam Observational Study. Front Pharmacol. 2017;8:607. 44. Romera A, Peredpaya S, Shparyk Y, Bondarenko I, Mendonça Bariani G, Abdalla KC, et al. Bevacizumab biosimilar BEVZ92 versus reference bevacizumab in combination with FOLFOX or FOLFIRI as first-line treatment for metastatic colorectal cancer: a multicentre, open-label, randomised controlled trial. Lancet Gastroenterol Hepatol. 2018 Sep 24. pii:S2468-1253(18)30269-3. doi:10.1016/S2468–1253(18)30269-3. 45. Hauser W, Hansen E, Enck P. Nocebo phenomena in medicine: their relevance in everyday clinical practice. Dtsch Arztebl Int. 2012;109(26):459-65. 46. Ministerio de Salud Secretaria de Políticas, Regulación e Institutos A.NM.A.T. DISPOSICIóN ANMAT N° 7729 [homepage on the Internet]. [cited 2018 Oct 17]. Available from: http://www.anmat.gov.ar/webanmat/retiros/noviembre/
Author for correspondence: Francisco Fernández, MD, Infectious Diseases Specialist, Laboratorio Elea Phoenix, Gral. Juan Gregorio Lemos 2809 (B1613 AUE), Los Polvorines, Buenos Aires, Argentina
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